88 results on '"Dianna S. Howard"'
Search Results
2. Real-world outcomes of adult patients with acute lymphoblastic leukemia treated with a modified CALGB 10102 regimen
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Daniel R. Reed, Margaux Wooster, Scott Isom, Leslie R. Ellis, Dianna S. Howard, Megan Manuel, Sarah Dralle, Susan Lyerly, Rupali Bhave, Bayard L. Powell, and Timothy S. Pardee
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Hematology ,General Medicine - Published
- 2023
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3. Supplemental Materials from A Phase I Study of CPI-613 in Combination with High-Dose Cytarabine and Mitoxantrone for Relapsed or Refractory Acute Myeloid Leukemia
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Bayard L. Powell, Susan Lyerly, Sarah Dralle, Megan Manuel, David D. Hurd, Dianna S. Howard, Dmitriy Berenzon, Leslie R. Ellis, Wei Zhang, Guangxu Jin, Jeff W. Chou, Lance D. Miller, Lais P. Ghiraldeli, Scott Isom, Kristin M. Pladna, Rebecca G. Anderson, and Timothy S. Pardee
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Figure S1. Dose escalation schema. Figure S2. Acetyl-CoA synthetase is expressed in OCI-AML3 and MFL2 cells. Figure S3 Acetate and methyl-succinate rescue of CPI-613 cytotoxicity. Figure S4. Treatment schema. Figure S5. Efficacy of HiDAC, mitoxantrone and CPI-613. Figure S6. Baseline bone marrow mononuclear cell gene expression profiles of responders (n=10) versus nonresponders (n=7). Figure S7. SOD2 expression levels are higher in non-responders Figure S8. SOD2 confers resistance to CPI-613. Figure S9. Mutational analysis from RNA sequence data of baseline marrow samples. Supplemental Table 1. Dose and Response by Patient Supplementary Table 2. Gene ontology enrichment analysis of genes overexpressed in responding patients
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- 2023
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4. Data from A Phase I Study of CPI-613 in Combination with High-Dose Cytarabine and Mitoxantrone for Relapsed or Refractory Acute Myeloid Leukemia
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Bayard L. Powell, Susan Lyerly, Sarah Dralle, Megan Manuel, David D. Hurd, Dianna S. Howard, Dmitriy Berenzon, Leslie R. Ellis, Wei Zhang, Guangxu Jin, Jeff W. Chou, Lance D. Miller, Lais P. Ghiraldeli, Scott Isom, Kristin M. Pladna, Rebecca G. Anderson, and Timothy S. Pardee
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Purpose: CPI-613, a lipoate analogue that inhibits pyruvate dehydrogenase (PDH) and α-ketogluterate dehydrogenase (KGDH), has activity in patients with myeloid malignancies. This study explored the role of mitochondrial metabolism in chemotherapy response and determined the MTD, efficacy, and safety of CPI-613 combined with high-dose cytarabine and mitoxantrone in patients with relapsed or refractory acute myeloid leukemia.Experimental Design: The role of mitochondrial response to chemotherapy was assessed in cell lines and animal models. A phase I study of CPI-613 plus cytarabine and mitoxantrone was conducted in patients with relapsed or refractory AML.Results: Exposure to chemotherapy induced mitochondrial oxygen consumption that depended on PDH. CPI-613 sensitized AML cells to chemotherapy indicating that mitochondrial metabolism is a source of resistance. Loss of p53 did not alter response to CPI-613. The phase I study enrolled 67 patients and 62 were evaluable for response. The overall response rate was 50% (26CR+5CRi/62). Median survival was 6.7 months. In patients over 60 years old, the CR/CRi rate was 47% (15/32) with a median survival of 6.9 months. The response rate for patients with poor-risk cytogenetics also was encouraging with 46% (11/24 patients) achieving a CR or CRi. RNA sequencing analysis of a subset of baseline bone marrow samples revealed a gene expression signature consistent with the presence of B cells in the pretreatment marrow of responders.Conclusions: The addition of CPI-613 to chemotherapy is a promising approach in older patients and those with poor-risk cytogenetics. Clin Cancer Res; 24(9); 2060–73. ©2018 AACR.
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- 2023
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5. Stakeholder‐informed conceptual framework for financial burden among adolescents and young adults with cancer
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Chandylen L Nightingale, Bryce B. Reeve, Denisha Little-Greene, Suzanne C. Danhauer, Nicole Puccinelli-Ortega, Mollie Rose Canzona, John M. Salsman, Reginald D. Tucker-Seeley, and Dianna S. Howard
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Adolescent ,media_common.quotation_subject ,Psycho-oncology ,Financial Stress ,Experimental and Cognitive Psychology ,Article ,Young Adult ,Indirect costs ,Cancer Survivors ,Neoplasms ,Adaptation, Psychological ,Health care ,Humans ,Survivors ,Socioeconomic status ,media_common ,Finance ,business.industry ,Stakeholder ,humanities ,Psychiatry and Mental health ,Oncology ,Conceptual framework ,Feeling ,business ,Psychology ,Psychosocial - Abstract
Background Cancer and its treatments can result in substantial financial burden that may be especially distressing for adolescents and young adults (AYAs) since they are at a developmental stage focused on completing one's education and establishing independence. The purpose of this study was to develop a conceptual model of financial burden among AYA cancer patients to inform development of a financial burden measure. Methods In-depth concept elicitation interviews were conducted with a purposive-selected stakeholder sample (36 AYAs and 36 AYA oncology health care providers). The constant comparative method was used to identify themes that illustrate AYAs' experience of financial burden by stakeholder groups. Results Eleven financial burden themes emerged: (1) impact of socioeconomic status and age; (2) significant cancer costs; (3) indirect cost "ripple effects"; (4) limited awareness of costs (adolescents); (5) emotional impact; (6) feeling overwhelmed navigating the health care system; (7) treatment decision modifications; (8) reducing spending; (9) coping strategies; (10) financial support; and (11) long-lasting impact. The conceptual model highlights the importance of material, psychosocial, and behavioral domains of financial burden with an emphasis on phase along the cancer continuum and developmental stage in the experience of financial burden for AYAs. Conclusions Issues presented in the voice of AYA patients and providers highlight the profound impact of financial burden in this survivor group. The next step in this work will be to develop and test a patient-reported measure of financial burden among AYA cancer survivors.
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- 2021
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6. CMV Infection in Hematopoietic Stem Cell Transplantation: Prevention and Treatment Strategies
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Niyati Jakharia, David J. Riedel, and Dianna S. Howard
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Cultural Studies ,Oncology ,Linguistics and Language ,History ,medicine.medical_specialty ,medicine.medical_treatment ,T cell ,Hematopoietic stem cell transplantation ,medicine.disease_cause ,Language and Linguistics ,Letermovir ,Immune system ,Immunity ,Internal medicine ,medicine ,Transplant/Immunocompromised Hosts (M Morales, Section Editor) ,business.industry ,virus diseases ,Maribavir ,Cytomegalovirus ,Clinical trial ,medicine.anatomical_structure ,Anthropology ,business ,CMV infection ,medicine.drug - Abstract
Purpose of Review Cytomegalovirus (CMV) remains a major cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation (Allo-HSCT). New strategies and methods for prevention and management of CMV infection are urgently needed. We aim to review the new developments in diagnostics, prevention, and management strategies of CMV infection in Allo-HSCT recipients. Recent Findings The approval of the novel anti-CMV drug letermovir in 2017 has led to an increase in the use of antiviral prophylaxis as a preferred approach for prevention in many centers. Real-world studies have shown efficacy similar to the clinical trial. CMV-specific T cell-mediated immunity assays identify patients with immune reconstitution and predict disease progression. Phase 2 trials of maribavir have shown its efficacy as preemptive therapy and treatment of resistant and refractory CMV infections. Adoptive T cell therapy is an emerging option for treatment of refractory and resistant CMV. Of the different CMV vaccine trials, PepVax has shown promising results in a phase 1 trial. Summary CMV cell-mediated immunity assays have potential to be used as an adjunctive test to develop individualized management plan by identifying the patients who develop immune reconstitution; however, further prospective interventional studies are needed. Maribavir and adoptive T cell therapy are promising new therapies for treatment of CMV infections. CMV vaccine trials for prevention are also under way.
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- 2021
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7. Haploidentical Transplant Using a Novel Preparative Regimen: An Update on a New Standard of Care for Patients without HLA Matched Donors
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Anne Wofford, Mary B Seegars, Jonathan Lambird, Rakhee Vaidya, Scott Isom, LeAnne Kennedy, Zachariah A McIver, and Dianna S. Howard
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Transplantation ,Molecular Medicine ,Immunology and Allergy ,Cell Biology ,Hematology - Published
- 2023
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8. A Pilot Phase II Study of the Feasibility and Efficacy of Vincristine Sulfate Liposome Injection in Patients With Relapsed or Refractory Acute Myeloid Leukemia
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Susan Lyerly, Megan Manuel, Rupali Bhave, Leslie R. Ellis, Ryan Woods, Timothy S. Pardee, Mary Beth Seegars, Bayard L. Powell, Dianna S. Howard, and Sarah Dralle
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Oncology ,medicine.medical_specialty ,Vincristine ,Constipation ,Vincristine Sulfate Liposome ,Relapsed ,03 medical and health sciences ,0302 clinical medicine ,Pharmacokinetics ,Refractory ,Internal medicine ,medicine ,Acute myeloid leukemia ,business.industry ,Myeloid leukemia ,Clinical trial ,030220 oncology & carcinogenesis ,Toxicity ,Original Article ,Therapy ,medicine.symptom ,business ,030217 neurology & neurosurgery ,medicine.drug - Abstract
Background: Resistance to therapy and a poor outcome characterize relapsed or refractory acute myeloid leukemia (AML). There is a clear need for additional palliative approaches with acceptable toxicities. Vincristine sulfate liposome injection (VSLI) confers enhanced pharmacokinetics and activity when compared to the parent compound. It is effective and well tolerated in heavily pretreated acute lymphoblastic leukemia (ALL) patients. Preclinically VSLI has activity in vincristine-resistant cancers. As relapsed or refractory AML patients would have minimal exposure to vincristine it was hypothesized that VSLI would be well tolerated and may have activity. Methods: A pilot phase II clinical trial was conducted. Five patients with relapsed or refractory disease were treated using the Food and Drug Administration (FDA)-approved dose and schedule. Results: Of the five patients treated none completed more than one cycle; there were no responses and two patients did not complete one cycle of therapy. Surprisingly, three of the five patients had treatment-related constipation, and two had neuropathy consistent with the known toxicities of VSLI. Given the toxicity and lack of response, the trial was terminated early. Conclusions: VSLI had no activity against relapsed or refractory AML in this limited, single institution dataset. J Hematol. 2021;10(1):1-7 doi: https://doi.org/10.14740/jh771
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- 2021
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9. Financial burden for caregivers of adolescents and young adults with cancer
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Chandylen L. Nightingale, Mollie R. Canzona, Suzanne C. Danhauer, Bryce B. Reeve, Dianna S. Howard, Reginald D. Tucker‐Seeley, Shannon L. S. Golden, Denisha Little‐Greene, Michael E. Roth, David E. Victorson, and John M. Salsman
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Psychiatry and Mental health ,Young Adult ,Oncology ,Adolescent ,Cancer Survivors ,Caregivers ,Neoplasms ,COVID-19 ,Humans ,Experimental and Cognitive Psychology ,Financial Stress - Abstract
Adolescent and young adult (AYA) cancer survivors are vulnerable to cancer-related financial burden, which is likely shared by their caregivers. This study aims to enhance an existing conceptual model of financial burden by conducting concept elicitation interviews with caregivers to generate knowledge that can be translated to inform instrumental and psychosocial support in cancer care.Qualitative concept elicitation interviews were conducted with 24 caregivers of AYA cancer survivors (caregivers of adolescents, n = 12; caregivers of emerging adults, n = 12) recruited from four sites. Constant comparative methods were used to identify themes, and results were interpreted and organized into domains of the conceptual model. We also explored COVID-19 related financial impacts among a subset (n = 12) of caregivers.Seven themes emerged, which varied by age group and strengthened the conceptualization of the model. Themes centered on: (1) direct and indirect costs of cancer; (2) impact of socioeconomic status on financial burden; (3) caregiver desire to shield AYAs from distress due to financial burden; (4) strategies to manage cancer-related costs; (5) worries about AYAs' financial future; (6) seeking and receiving financial support; and (7) navigating the healthcare system. Findings also revealed that COVID-19 exacerbates financial burden for some caregivers.Building upon our prior work, we have adapted the conceptual model of financial burden to reflect perspectives of AYAs, oncology providers, and now, caregivers. An important next step is to develop a reliable and valid self-report measure of financial burden among caregivers of AYA cancer survivors.
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- 2022
10. Re-induction therapy in adult patients with acute myeloid leukemia with ≤20 % blasts: A retrospective cohort study
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Kavya K. Kannan, Susan Lyerly, Dianna S. Howard, Leslie R. Ellis, Timothy S. Pardee, Allison Winter, Bayard L. Powell, Heidi D. Klepin, Rupali Bhave, Paz Vellanki, Bernard Tawfik, Megan Manuel, Scott Isom, and Sarah Dralle
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Oncology ,Male ,Cancer Research ,medicine.medical_specialty ,Article ,Internal medicine ,Induction therapy ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Humans ,Aged ,Retrospective Studies ,Adult patients ,business.industry ,Myeloid leukemia ,Retrospective cohort study ,Hematology ,Induction Chemotherapy ,Middle Aged ,Prognosis ,Survival Rate ,Leukemia, Myeloid, Acute ,Female ,business ,Blast Crisis ,Follow-Up Studies - Published
- 2021
11. A Multi-Center Collaborative Study of Outcomes of TP53-Mutated MDS/AML Patients Following Allogeneic HCT
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Michael Byrne, Tony Kurian, Dilan Patel, Roni Tamari, Sanghee Hong, Haitham Abdelhakim, Victoria Klein, Patricio Rojas, Raksha Madhavan, Andrew Kent, Aaron C. Logan, Catherine J. Lee, Muhammad Husnain, Benjamin Manning, Nicholas Tschernia, Ajoy Dias, Daniel Margalski, Benjamin Goldenson, Nathalie D. Byrne, Heidi Chen, Kseniya Petrova-Drus, Salyka Sengsayadeth, Aaron Goodman, Dianna S. Howard, William A. Wood, Saar Gill, Antonio Jimenez Jimenez, Jonathan A. Gutman, Lohith Gowda, Leland Metheny III, Bhavana Bhatnagar, Betty K. Hamilton, Asmita Mishra, and Michael R. Savona
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Transplantation ,Molecular Medicine ,Immunology and Allergy ,Cell Biology ,Hematology - Published
- 2022
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12. Haploidentical Transplant Using a Novel Preparative Regimen: A New Standard of Care for Patients without HLA Matched Donors
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Anne Wofford, Mary B Seegars, Jonathan Lambird, Rakhee Vaidya, Scott Isom, LeAnne Kennedy, Zachariah A McIver, and Dianna S. Howard
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Transplantation ,Molecular Medicine ,Immunology and Allergy ,Cell Biology ,Hematology - Published
- 2022
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13. Feasibility Study of Telemedicine for Outpatient Chimeric Antigen Receptor (CAR) T-Cell Program
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Rakhee Vaidya, Rebecca Damron, Melanie Hooker, Michelle Payne, Mary B Seegars, Dianna S. Howard, and Joshua D Brown
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Transplantation ,Molecular Medicine ,Immunology and Allergy ,Cell Biology ,Hematology - Published
- 2022
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14. Belumosudil for chronic graft-versus-host disease after 2 or more prior lines of therapy: the ROCKstar Study
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Iskra Pusic, Steven Z. Pavletic, John P. Galvin, Amandeep Salhotra, Zhongming Yang, Dianna S. Howard, Madan Jagasia, Ayman Saad, Wanxing Chai-Ho, Bruce R. Blazar, Aaron C Logan, Amelia Langston, Corey Cutler, Trent P Wang, Jonathan Ieyoub, Sally Arai, Marcello Rotta, Mukta Arora, Jane L. Liesveld, Asaf Alavi, David Eiznhamer, Mark B. Juckett, Annie Im, Aravind Ramakrishnan, Behyar Zoghi, Sunil Abhyankar, John J. Ryan, Nirav N. Shah, Stephanie J. Lee, Laurie S. Green, Zachariah DeFilipp, Heidi Krenz, Rohtesh S. Mehta, Harlan Waksal, Sanjay K. Aggarwal, Carlos R. Bachier, Levanto Schachter, Aleksandr Lazaryan, and Olivier Schueller
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Adult ,Male ,Ruxolitinib ,medicine.medical_specialty ,business.operation ,Nausea ,Immunology ,Graft vs Host Disease ,Biochemistry ,law.invention ,Young Adult ,Randomized controlled trial ,law ,Internal medicine ,Acetamides ,medicine ,Clinical endpoint ,Humans ,Adverse effect ,Protein Kinase Inhibitors ,Aged ,Response rate (survey) ,rho-Associated Kinases ,Errata ,business.industry ,Mallinckrodt ,Cell Biology ,Hematology ,Middle Aged ,Confidence interval ,Treatment Outcome ,Female ,medicine.symptom ,business ,medicine.drug - Abstract
Introduction: Belumosudil (KD025) is a novel oral selective rho-associated coiled-coil kinase 2 (ROCK2) inhibitor specifically designed for the treatment of cGVHD, an immune-mediated inflammatory and fibrotic disorder. In a previous dose-finding study (KD025-208, N=54), two-thirds of patients, including those with fibrotic and inflammatory manifestations, achieved a partial or complete response with belumosudil. Herein, we report on the top-line results (6 months after the last patient in) from the pivotal phase 2 trial (ROCKstar [KD025-213], N=132). Methods: This phase 2, open-label, randomized, multicenter study evaluated belumosudil 200 mg QD (n=66) and BID (n=66) in patients with cGVHD who received 2 to 5 prior lines of therapy (LOT). Treatment continued until clinically significant progression of cGVHD. The primary end point was overall response rate (ORR), defined per the 2014 National Institutes of Health Consensus Criteria. Additional end points included duration of response (DOR), Lee Symptom Scale (LSS) score, failure-free survival (FFS), corticosteroid (CS) dose reductions and overall survival. The study was powered such that the lower bound of the 95% confidence interval (CI) excludes 30%, with appropriate multiplicity adjustment. Results: At enrollment, the median age was 56 years, the median time from cGVHD diagnosis to enrollment was 29 months, 67% of patients had severe cGVHD, 52% had ≥4 organs involved, 72% had received ≥3 prior LOT (including ibrutinib [n=46] or ruxolitinib [n=38]) and 73% were refractory to their last LOT. The baseline characteristics of both arms were well balanced. With a median follow-up of 8 months, the ORR (95% CI) with belumosudil 200 mg QD and BID was 73% (60%-83%) and 74% (62%-84%), respectively (Table 1). In patients who previously received ruxolitinib (29%), the ORR with belumosudil 200 mg QD and BID was 65% (41%-85%) and 72% (47%-90%), respectively. In patients who previously received ibrutinib (35%), the ORR with belumosudil 200 mg QD and BID was 73% (50%-89%) and 71% (49%-87%), respectively. High ORRs were seen in all patient subgroups, regardless of length of time from diagnosis to treatment, including those with severe cGVHD, involvement of ≥4 organs and a refractory response to prior LOT (Figure 1). The response rate was similar across all affected organs. The median time to response was 4 weeks. Of responders, 49% have maintained response for ≥20 weeks. The median DOR has not yet been reached. Clinically meaningful improvement (≥7-point reduction) in LSS score on consecutive assessments was observed in 39% and 33% of patients in the QD and BID groups, respectively. Both responders (43%) and nonresponders (17%) experienced a clinically meaningful improvement in LSS score. FFS was 77% (69%-84%) at 6 months. CS and calcineurin inhibitor discontinuations were seen in 18% and 13% of patients, respectively. Belumosudil was well tolerated, with >95% relative dose intensity in 83% of patients. Drug discontinuation occurred in 10% of patients due to possible drug-related adverse events (AEs), 3% due to progression of underlying disease and 12% due to progression of cGVHD. AEs were consistent with those expected in patients with cGVHD receiving CS and other immunosuppressants (Table 2). Common AEs included fatigue (32%), diarrhea (29%), nausea (26%), cough (24%), dyspnea (24%), upper respiratory tract infection (23%), peripheral edema (21%) and headache (20%). At least 1 serious AE occurred in 34% of patients. Twenty-three percent of patients had at least 1 liver-related investigation; the most common was increased gamma-glutamyltransferase (11%), and only 1 patient showed an increase in bilirubin. Eight patients died during the study; 5 due to AEs (1 possibly related to belumosudil) and 3 during long-term follow-up (>28 days after last dose). There were no reports of cytomegalovirus reactivation or infection. Conclusion: Treatment with belumosudil at both doses resulted in high ORRs across key subgroups, meeting the primary end point of this pivotal randomized trial in cGVHD. Responses were durable and clinically meaningful, irrespective of patient and cGVHD characteristics, and were seen in patients who previously received ruxolitinib and ibrutinib. Belumosudil was well tolerated, with limited and manageable AEs. Further studies will evaluate its use earlier in disease management. The 12-month data analysis will be presented at ASH 2020. Download : Download high-res image (508KB) Download : Download full-size image Disclosures Cutler: Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees; Kadmon: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz: Consultancy, Membership on an entity's Board of Directors or advisory committees; Medsenic: Consultancy, Membership on an entity's Board of Directors or advisory committees; Generon: Consultancy, Membership on an entity's Board of Directors or advisory committees; Mesoblast: Consultancy, Membership on an entity's Board of Directors or advisory committees. Lee: Pfizer: Consultancy, Research Funding; Incyte: Consultancy, Research Funding; Amgen: Research Funding; Kadmon: Research Funding; AstraZeneca: Research Funding; Novartis: Research Funding; Takeda: Research Funding; Syndax: Research Funding. Rotta: Merck: Speakers Bureau; Jazz Pharma: Speakers Bureau. Ramakrishnan: Amgen: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Cigna: Honoraria. Eiznhamer: Kadmon Corporation, LLC: Current Employment, Current equity holder in publicly-traded company. Schueller: Kadmon Corporation, LLC: Current Employment, Current equity holder in publicly-traded company. Yang: Kadmon Corporation, LLC: Current Employment, Current equity holder in publicly-traded company. Green: Kadmon Corporation, LLC: Current Employment, Current equity holder in publicly-traded company. Aggarwal: Kadmon Corporation, LLC: Consultancy; Angiocrine Bioscience, Inc: Current Employment, Other: stock options. Blazar: BlueRock Therapeutics: Research Funding; BlueRock Therapeuetic: Consultancy; Fate Therapeutics Inc.: Research Funding; Magenta Therapeutics: Consultancy; Childrens' Cancer Research Fund: Research Funding; KidsFirst Fund: Research Funding; Tmunity: Other: Co-founder. Jagasia: Ocugen: Other; Mallinckrodt: Research Funding; Janssen: Research Funding.
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- 2021
15. Systematic review of financial burden assessment in cancer: Evaluation of measures and utility among adolescents and young adults and caregivers
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Reginald D. Tucker-Seeley, Laurie E. McLouth, Dianna S. Howard, Denisha Little-Greene, Edward H. Ip, Suzanne C. Danhauer, John M. Salsman, Chandylen L Nightingale, Kristin Bingen, Bryce B. Reeve, Christabel K. Cheung, and Justin B. Moore
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Cancer Research ,Adolescent ,Psychometrics ,Validity ,Financial Stress ,CINAHL ,PsycINFO ,Cochrane Library ,Article ,03 medical and health sciences ,Young Adult ,0302 clinical medicine ,Quality of life (healthcare) ,Neoplasms ,Surveys and Questionnaires ,Medicine ,Humans ,030212 general & internal medicine ,Young adult ,Finance ,business.industry ,Stressor ,Reproducibility of Results ,Oncology ,Caregivers ,030220 oncology & carcinogenesis ,business ,Psychosocial - Abstract
The cost of cancer care is rising and represents a stressor that has significant and lasting effects on quality of life for many patients and caregivers. Adolescents and young adults (AYAs) with cancer are particularly vulnerable. Financial burden measures exist but have varying evidence for their validity and reliability. The goal of this systematic review is to summarize and evaluate measures of financial burden in cancer and describe their potential utility among AYAs and their caregivers. To this end, the authors searched PubMed, Embase, the Cochrane Library, CINAHL, and PsycINFO for concepts involving financial burden, cancer, and self-reported questionnaires and limited the results to the English language. They discarded meeting abstracts, editorials, letters, and case reports. The authors used standard screening and evaluation procedures for selecting and coding studies, including consensus-based standards for documenting measurement properties and study quality. In all, they screened 7250 abstracts and 720 full-text articles to identify relevant articles on financial burden. Eighty-six articles met the inclusion criteria. Data extraction revealed 64 unique measures for assessing financial burden across material, psychosocial, or behavioral domains. One measure was developed specifically for AYAs, and none were developed for their caregivers. The psychometric evidence and study qualities revealed mixed evidence of methodological rigor. In conclusion, several measures assess the financial burden of cancer. Measures were primarily designed and evaluated in adult patient populations with little focus on AYAs or caregivers despite their increased risk of financial burden. These findings highlight opportunities to adapt and test existing measures of financial burden for AYAs and their caregivers.
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- 2021
16. Phase II trial of cytarabine and mitoxantrone with devimistat in acute myeloid leukemia
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Rebecca, Anderson, Lance D, Miller, Scott, Isom, Jeff W, Chou, Kristin M, Pladna, Nathaniel J, Schramm, Leslie R, Ellis, Dianna S, Howard, Rupali R, Bhave, Megan, Manuel, Sarah, Dralle, Susan, Lyerly, Bayard L, Powell, and Timothy S, Pardee
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Leukemia, Myeloid, Acute ,Treatment Outcome ,Antineoplastic Combined Chemotherapy Protocols ,Cytarabine ,Humans ,Caprylates ,Mitoxantrone ,Sulfides ,Aged - Abstract
Devimistat is a TCA cycle inhibitor. A previously completed phase I study of devimistat in combination with cytarabine and mitoxantrone in patients with relapsed or refractory AML showed promising response rates. Here we report the results of a single arm phase II study (NCT02484391). The primary outcome of feasibility of maintenance devimistat following induction and consolidation with devimistat in combination with high dose cytarabine and mitoxantrone was not met, as maintenance devimistat was only administered in 2 of 21 responders. The secondary outcomes of response (CR + CRi) and median survival were 44% (21/48) and 5.9 months respectively. There were no unexpected toxicities observed. An unplanned, post-hoc analysis of the phase I and II datasets suggests a trend of a dose response in older but not younger patients. RNA sequencing data from patient samples reveals an age-related decline in mitochondrial gene sets. Devimistat impairs ATP synthesis and we find a correlation between mitochondrial membrane potential and sensitivity to chemotherapy. Devimistat also induces mitochondrial reactive oxygen species and turnover consistent with mitophagy. We find that pharmacological or genetic inhibition of mitochondrial fission or autophagy sensitizes cells to devimistat. These findings suggest that an age related decline in mitochondrial quality and autophagy may be associated with response to devimistat however this needs to be confirmed in larger cohorts with proper trial design.
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- 2020
17. Devimistat Induces Mitophagy and Chemosensitization Resulting in Increases in Survival in Older But Not Younger AML Patients
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Susan Lyerly, Leslie R. Ellis, Rupali Bhave, Jeff W. Chou, Lance D. Miller, Megan Manuel, Kristin M. Pladna, Scott Isom, Sarah Dralle, Rebecca G. Anderson, Nathaniel J. Schramm, Timothy S. Pardee, Bayard L. Powell, and Dianna S. Howard
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Mitoxantrone ,business.industry ,Mitochondrial Turnover ,Chemosensitization ,Mitophagy ,Cancer research ,Cytarabine ,Medicine ,Mitochondrion ,business ,Gene ,Metformin ,medicine.drug - Abstract
Devimistat is a novel TCA cycle inhibitor being studied in combination with cytarabine and mitoxantrone in patients with relapsed or refractory AML. A combined analysis of the phase I and II datasets was conducted to determine the optimal phase III dose. A dose response in older but not younger patients was observed. Gene set enrichment analysis of RNA sequence data from patient samples revealed an age-related decline in mitochondrial function and biogenesis. In cell line models there was a strong direct correlation between the baseline mitochondrial membrane potential and the sensitizing effects of devimistat and metformin could render resistant cells sensitive. Additional mechanistic studies revealed that TCA cycle inhibition with devimistat or by genetic manipulation induced mitochondrial turnover. Pharmacological or genetic inhibition of mitophagy sensitized AML cells to devimistat. These data support a model whereby devimistat preferentially benefits older patients with reduced mitochondrial quality and biosynthetic capacity.
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- 2020
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18. Final outcomes of escalated melphalan 280 mg/m2 with amifostine cytoprotection followed autologous hematopoietic stem cell transplantation for multiple myeloma: high CR and VGPR rates do not translate into improved survival
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A. Badros, Dianna S. Howard, Barry R. Meisenberg, Donna E. Reece, David H. Vesole, Joanne Filicko-O'Hara, Jasleen K Randhawa, Neal Flomenberg, Parameswaran Hari, Aaron P. Rapoport, and Gordon L. Phillips
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Oncology ,Melphalan ,Transplantation ,medicine.medical_specialty ,Chemotherapy ,business.industry ,medicine.medical_treatment ,Hematology ,Amifostine ,Hematopoietic stem cell transplantation ,medicine.disease ,03 medical and health sciences ,0302 clinical medicine ,hemic and lymphatic diseases ,030220 oncology & carcinogenesis ,Internal medicine ,medicine ,Autologous transplantation ,business ,Multiple myeloma ,030215 immunology ,medicine.drug ,Preparative Regimen - Abstract
The most common preparative regimen for autologous transplantation (ASCT) in myeloma (MM) consists of melphalan 200 mg/m2 (MEL 200). Higher doses of melphalan 220–260 mg/m2, although relatively well tolerated, have not shown significant improvement in clinical outcomes. Several approaches have been pursued in the past to improve CR rates, including poly-chemotherapy preparative regimens, tandem ASCT, consolidation, and/or maintenance therapy. Since there is a steep dose–response effect for intravenous melphalan, we evaluated an alternative single ASCT strategy using higher-dose melphalan at 280 mg/m2 (MEL 280) with amifostine as a cytoprotectant as the maximum tolerated dose determined in an earlier phase I dose escalation trial. We report the final long-term outcomes of MM patients who underwent conditioning with MEL 280 with amifostine cytoprotection followed by ASCT. Although the complete response rate was quite high in the era pre-dating the routine use of novel therapies (proteasome inhibitors, immunomodulatory agents) (49%), the progression-free survival was a disappointing 22 months. The implications of this dichotomy between the excellent depth of ASCT response and progression-free survival are discussed.
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- 2018
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19. Age adjusted hematopoietic stem cell transplant comorbidity index predicts survival in a T-cell depleted cohort
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Dianna S. Howard, Gerhard C. Hildebrandt, Roger H. Herzig, Meng Liu, Gregory Monohan, Swati Yalamanchi, Hayder Saeed, Zartash Gul, and Emily Van Meter
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Adult ,Male ,medicine.medical_specialty ,T-Lymphocytes ,medicine.medical_treatment ,Population ,Age adjustment ,Comorbidity ,Hematopoietic stem cell transplantation ,lcsh:RC254-282 ,Disease-Free Survival ,Lymphocyte Depletion ,03 medical and health sciences ,0302 clinical medicine ,Risk Factors ,Neoplasms ,Internal medicine ,medicine ,Humans ,education ,Survival rate ,Aged ,Retrospective Studies ,education.field_of_study ,lcsh:RC633-647.5 ,business.industry ,Age Factors ,Hematopoietic Stem Cell Transplantation ,Retrospective cohort study ,lcsh:Diseases of the blood and blood-forming organs ,Hematology ,General Medicine ,Middle Aged ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,Allografts ,medicine.disease ,Survival Rate ,Transplantation ,Oncology ,030220 oncology & carcinogenesis ,Cohort ,Female ,business ,030215 immunology - Abstract
Objectives: Allogeneic hematopoietic stem cell transplant (HCT) continues to evolve with the treatment in higher risk patient population. This practice mandates stringent update and validation of risk stratification prior to undergoing such a complex and potentially fatal procedure. We examined the adoption of the new comorbidity index (HCT-CI/Age) proposed by the Seattle group after the addition of age variable and compared it to the pre-transplant assessment of mortality (PAM) that already incorporates age as part of its evaluation criteria. Methods: A retrospective analysis of adult patients who underwent HCT at our institution from January 2010 through August 2014 was performed. Kaplan-Meier’s curve, log-rank tests, Cox model and Pearson correlation was used in the analysis. Results: Of the 114 patients that underwent allogeneic transplant in our institution, 75.4% were ≥40 years old. More than 58% had a DLCO ≤80%. Although scores were positively correlated (correlation coefficient 0.43, p
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- 2018
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20. A Phase I Study of CPI-613 in Combination with High-Dose Cytarabine and Mitoxantrone for Relapsed or Refractory Acute Myeloid Leukemia
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Leslie R. Ellis, Susan Lyerly, Dmitriy Berenzon, Megan Manuel, Wei Zhang, Dianna S. Howard, Timothy S. Pardee, Sarah Dralle, Bayard L. Powell, Rebecca G. Anderson, Jeff W. Chou, Scott Isom, Lance D. Miller, Kristin M. Pladna, Lais P. Ghiraldeli, Guangxu Jin, and David D. Hurd
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Male ,0301 basic medicine ,Oncology ,Cancer Research ,Myeloid ,Biopsy ,medicine.medical_treatment ,Mice ,0302 clinical medicine ,Bone Marrow ,Recurrence ,Antineoplastic Combined Chemotherapy Protocols ,Cytarabine ,Myeloid leukemia ,Middle Aged ,Mitochondria ,Leukemia, Myeloid, Acute ,Leukemia ,Treatment Outcome ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Retreatment ,Female ,Caprylates ,medicine.drug ,Adult ,medicine.medical_specialty ,Cell Respiration ,Sulfides ,Article ,Cell Line ,Young Adult ,03 medical and health sciences ,Oxygen Consumption ,Internal medicine ,medicine ,Animals ,Humans ,Aged ,Neoplasm Staging ,Chemotherapy ,Mitoxantrone ,business.industry ,Cancer ,medicine.disease ,030104 developmental biology ,Drug Resistance, Neoplasm ,Bone marrow ,Neoplasm Grading ,business ,Biomarkers - Abstract
Purpose: CPI-613, a lipoate analogue that inhibits pyruvate dehydrogenase (PDH) and α-ketogluterate dehydrogenase (KGDH), has activity in patients with myeloid malignancies. This study explored the role of mitochondrial metabolism in chemotherapy response and determined the MTD, efficacy, and safety of CPI-613 combined with high-dose cytarabine and mitoxantrone in patients with relapsed or refractory acute myeloid leukemia. Experimental Design: The role of mitochondrial response to chemotherapy was assessed in cell lines and animal models. A phase I study of CPI-613 plus cytarabine and mitoxantrone was conducted in patients with relapsed or refractory AML. Results: Exposure to chemotherapy induced mitochondrial oxygen consumption that depended on PDH. CPI-613 sensitized AML cells to chemotherapy indicating that mitochondrial metabolism is a source of resistance. Loss of p53 did not alter response to CPI-613. The phase I study enrolled 67 patients and 62 were evaluable for response. The overall response rate was 50% (26CR+5CRi/62). Median survival was 6.7 months. In patients over 60 years old, the CR/CRi rate was 47% (15/32) with a median survival of 6.9 months. The response rate for patients with poor-risk cytogenetics also was encouraging with 46% (11/24 patients) achieving a CR or CRi. RNA sequencing analysis of a subset of baseline bone marrow samples revealed a gene expression signature consistent with the presence of B cells in the pretreatment marrow of responders. Conclusions: The addition of CPI-613 to chemotherapy is a promising approach in older patients and those with poor-risk cytogenetics. Clin Cancer Res; 24(9); 2060–73. ©2018 AACR.
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- 2018
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21. Non-Relapse Mortality in TP53-Mutated MDS/AML - a Multi-Center Collaborative Study
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Michael R. Savona, Victoria Klein, Asmita Mishra, Bhavana Bhatnagar, Sanghee Hong, Dilan A Patel, Patricio Rojas, Benjamin H. Goldenson, Lohith Gowda, Roni Tamari, Salyka Sengsayadeth, Benjamin M Manning, Catherine J. Lee, Daniel Margalski, Tony Kurian, Raksha Madhavan, Andrew Kent, Kseniya Petrova-Drus, Haitham Abdelhakim, Dianna S. Howard, Saar Gill, Nicholas Tschernia, Leland Metheny, Betty K. Hamilton, Aaron C Logan, Ajoy Dias, Nathalie Byrne, Aaron M. Goodman, William A. Wood, Antonio M. Jimenez, Michael Byrne, Jonathan A. Gutman, Heidi Chen, and Muhammad Husnain
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Oncology ,medicine.medical_specialty ,business.industry ,Internal medicine ,Immunology ,Medicine ,Nonrelapse mortality ,Center (algebra and category theory) ,Cell Biology ,Hematology ,business ,Biochemistry - Abstract
Background: Patients with TP53 MUT MDS/AML experience poor clinical outcomes with high rates of disease recurrence and short overall survival (OS). Characterization of these individuals' post-HCT mortality is uniquely challenging due to competing risks from disease relapse and treatment toxicity. Transplant registries contain high-level outcomes data, however, there is a lack of detailed data in molecularly defined subsets of diease. This analysis was undertaken to bridge this gap. Methods: Allogeneic HCT recipients between 1/2014 and 12/2018 were retrospectively studied. Key inclusion criteria were TP53 MUT by NGS or deletion of chromosome 17/17p by FISH/cytogenetics. The primary outcome of non-relapse mortality (NRM) was defined as death from any cause other than disease with relapse as competing risk. Secondary outcomes for this analysis were OS, cumulative incidence of relapse (CIR), and relapse free survival (RFS). Relapse was defined as relapse/progression with NRM as competing risk. Results: 384 TP53 MUT MDS/AML patients were analyzed. 55% of patients were transplanted for AML, 41% received myeloablative conditioning (MAC), 39% had secondary MDS/AML, and 26% received prior chemo and/or radiation therapy (XRT). Median time from HCT to last follow-up was 321 days (range 8-2,385 days). Mutational data was available in 264 patients and cytogenetic data was available in 368 patients; 78% of patients had a complex karyotype (CK), 82% had TP53 missense mutations, and 74% had bi-allelic targeting of the TP53 gene. The incidence of all-grade acute and chronic GVHD (cGVHD) was 52% and 31%, respectively. One and 2 year OS was 48.5% and 30.9%, respectively. Estimated CIR at 1 and 2 years was 49% and 54.9%, respectively. The 1 year NRM was 13.7% and 2 year NRM was 18.1%. In multivariate analysis (MVA), there was no association between NRM and the clinical, molecular, or genetic features of TP53 MUT MDS/AML. HCT diagnosis of MDS (HR: 0.67, 95% CI: 0.46-0.97, p: 0.036), mono-allelic TP53 MUT (HR: 0.6, 95% CI: 0.39-0.94, p: 0.023), achievement of full donor PB chimerism (HR: 0.33, 95% CI: 0.14-0.85, p: 0.022), BM chimerism (HR: 0.33, 95% CI: 0.18-0.60, p: 0.003), and cGVHD (HR: 0.35, 95% CI: 0.23-0.51, p: In subgroup analysis, history of chemo and/or XRT increased NRM in AML (HR: 4.24, 95% CI: 1.35-13.39, p: 0.014). Pre-HCT TP53 MUT persistence by NGS (HR: 3.59, 95% CI: 1.43-9, p: 0.007) predicted for post-HCT relapse whereas pre-HCT CR (HR: 2.93, 95% CI: 1.54-5.59, p: 0.001) and full donor BM chimerism (HR: 0.14, 95% CI: 0.05-0.38, p: No significant NRM associations were identified in MDS. CK (HR: 5.04, 95% CI: 1.95-13.01, p: Conclusions: From this large multi-institutional cohort of TP53 MUT myeloid neoplasms, we report a low NRM rate, likely due to high rates of post-HCT relapse/progression. These data demonstrate associations between bi-allelic TP53m/CK and post-HCT outcomes. Our work highlights the importance donor chimerism after HCT and provides new understanding of the importance of chronic GVHD in TP53 MUT MDS/AML. Figure 1 Figure 1. Disclosures Byrne: Karyopharm: Research Funding. Logan: Amgen, Pfizer, AbbVie: Consultancy; Pharmacyclics, Astellas, Jazz, Kite, Kadmon, Autolus, Amphivena: Research Funding. Lee: CareDx: Membership on an entity's Board of Directors or advisory committees; Kadmon: Membership on an entity's Board of Directors or advisory committees; Kite: Membership on an entity's Board of Directors or advisory committees; Fresensius Kabi: Consultancy; Jazz,: Consultancy; Incyte: Research Funding. Goodman: Seattle Genetics: Consultancy, Speakers Bureau; EUSA Pharma: Consultancy, Honoraria. Gill: Interius Biotherapeutics: Current holder of stock options in a privately-held company, Research Funding; Novartis: Other: licensed intellectual property, Research Funding; Carisma Therapeutics: Current holder of stock options in a privately-held company, Research Funding. Jimenez: Takeda: Research Funding; AbbVie: Research Funding. Metheny: Pharmacosmos: Honoraria; Incyte: Speakers Bureau. Bhatnagar: Pfizer: Honoraria; Celgene: Honoraria; Novartis: Honoraria; Astellas: Honoraria; Cell Therapeutics: Honoraria, Research Funding; Kite: Honoraria; Karyopharm: Honoraria, Research Funding; Sumitomo Dainippon Pharma: Research Funding. Hamilton: Syndax: Membership on an entity's Board of Directors or advisory committees; Equilium: Membership on an entity's Board of Directors or advisory committees. Mishra: Novartis: Research Funding. Savona: BMS-Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; CTI: Consultancy, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Geron: Consultancy, Membership on an entity's Board of Directors or advisory committees; NOVARTIS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Ryvu: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sierra Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees; Taiho: Consultancy, Membership on an entity's Board of Directors or advisory committees; TG Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; ALX Oncology: Research Funding; Astex: Research Funding; Incyte: Research Funding.
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- 2021
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22. Outcomes Following Reinduction Therapy for Relapsed Acute Myeloid Leukemia Post Allogeneic Hematopoietic Cell Transplantation
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Brooke Laine Brown, LeAnne Kennedy, Brandi Anders, Rebecca Garcia Hunt, Dianna S. Howard, Maho Hibino, and Emily Johnson
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Oncology ,Transplantation ,medicine.medical_specialty ,Hematopoietic cell ,business.industry ,Myeloid leukemia ,Cell Biology ,Hematology ,Internal medicine ,Molecular Medicine ,Immunology and Allergy ,Medicine ,business - Published
- 2021
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23. Frontline Selinexor and Chemotherapy Is Highly Active in Older Adults with Acute Myeloid Leukemia (AML)
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Rupali Bhave, Timothy S. Pardee, Leslie R. Ellis, Bayard L. Powell, Megan Manuel, Kristin M. Pladna, Dianna S. Howard, Susan Lyerly, and Sarah Dralle
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Oncology ,medicine.medical_specialty ,Chemotherapy ,Randomization ,biology ,business.industry ,Daunorubicin ,medicine.medical_treatment ,Topoisomerase ,Immunology ,Phases of clinical research ,Myeloid leukemia ,Cell Biology ,Hematology ,Biochemistry ,Maintenance therapy ,Internal medicine ,medicine ,Cytarabine ,biology.protein ,business ,medicine.drug - Abstract
Background: Acute myeloid leukemia (AML) is an aggressive malignancy of the bone marrow characterized by resistance to treatment and dismal outcomes, especially in the elderly. Novel approaches are desperately needed. Exportin 1 (XPO1) is involved in the selective nuclear export of certain proteins and RNA species. It is overexpressed in a subset of AML, conferring an adverse prognosis. Selinexor is a small-molecule inhibitor of XPO1 with activity in AML. Selinexor sensitizes AML cells to anthracyclines by retaining topoisomerase II in the nucleus resulting in increased DNA strand breaks. Furthermore, selinexor has shown encouraging results when combined with chemotherapy in AML. This abstract reports the ongoing results of a randomized phase II study of induction and consolidation with or without selinexor in newly diagnosed patients with AML, 60 years of age or older and preclinical studies to assess the mechanisms of chemo-sensitization. Methods: Patients 60 years of age or older with newly diagnosed de novo AML were randomized 3:1 between 7+3+selinexor or 7+3. Responding patients could go on to high dose cytarabine consolidation with or without selinexor as per initial randomization. Patients in the selinexor arm who completed all consolidation could then move to maintenance therapy with selinexor alone. Induction consisted of cytarabine 100 mg/m2/d by continuous infusion for 7 days and daunorubicin 60 mg/m2 on days 1-3. Consolidation consisted of cytarabine at 1.5 gm/m2 given Q12 hours days 1-3 with G-CSF given 24 hours following the last dose of cytarabine. Selinexor was dosed at 60 mg PO on days 1, 3, 8, 10, 15 and 17 during induction and consolidation and on days 1 and 8 every 21 days during maintenance. Preclinical studies were conducted with murine AML cell lines. Results: Twenty-seven of a planned twenty-eight patients were enrolled to date. Of the 27 evaluable patients, 20 were randomized to the selinexor arm and 7 to the control arm. Baseline demographics are listed in Table 1. In the standard arm, both 30- and 60-day mortality were 14% (1/7). In the selinexor arm, both 30- and 60-day mortality were 10% (2/20). In the standard arm, 43% (3/7) of patients achieved a complete remission (CR) or complete remission with incomplete count recovery (CRi). Of the 3 responders 1 has gone on to transplant. In the selinexor arm, 85% (17/20) of patients achieved a CR or CRi. Of the 17 responders, 4 have gone on to transplant. Progression free and overall survival both favor the selinexor arm with trends towards significance despite the small size of the trial (Figure 1 and Table 2). No difference in the AE profile was noted between arms and no unexpected side effects were observed. Selinexor induces retention of topoisomerase II in the nucleus increasing sensitivity to anthracyclines. To determine if selinexor sensitized to cytarabine viability assays using murine AML cell lines were done (Figure 2A). Selinexor significantly sensitized both cell lines to cytarabine. AML cells increase mitochondrial oxygen consumption in response to cytarabine leading to resistance. The ability of selinexor to interfere with this response was assessed using Seahorse flux analysis. AML cells treated with cytarabine for 16 hours showed a diminished mitochondrial oxygen response when co-treated with selinexor (Figure 2B). Conclusions: Selinexor in combination with standard induction and consolidation therapy appears highly active in older patients with de novo AML. Selinexor may increase response to cytarabine by interfering with nuclear-mitochondrial communication. Enrollment is ongoing. Disclosures Pardee: Rafael Pharmaceuticals: Consultancy; AbbVie: Consultancy; Genentech, Inc.: Consultancy; BMS: Consultancy, Honoraria, Speakers Bureau; Karyopharm: Research Funding; Rafael: Research Funding; Celgene: Consultancy, Honoraria, Speakers Bureau; Amgen: Honoraria, Speakers Bureau; Pharmacyclics: Speakers Bureau. Ellis:Rafael Pharmaceuticals: Consultancy. Howard:Jazz Pharmaceuticals: Consultancy. Powell:Jazz Pharmaceuticals: Consultancy, Other: Advisor, Research Funding; Genentech: Research Funding; Novartis: Research Funding; Pfizer: Research Funding; Rafael Pharmaceuticals: Consultancy, Other: Advisor, Research Funding. OffLabel Disclosure: Selinexor for the treatment of AML
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- 2020
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24. A symptom-adapted physical activity intervention during induction chemotherapy for older adults with acute myeloid leukemia (AML) to maintain physical function
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Wendy Demark-Wahnefried, Stephen B. Kritchevsky, Shannon L. Mihalko, Bayard L. Powell, Leslie R. Ellis, Jack Rejeski, Timothy S. Pardee, Heidi D. Klepin, Ann M. Geiger, Janet A. Tooze, and Dianna S. Howard
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Oncology ,Cancer Research ,medicine.medical_specialty ,business.industry ,Physical activity ,Psychological intervention ,Induction chemotherapy ,Myeloid leukemia ,Physical function ,Intervention (counseling) ,Internal medicine ,Induction therapy ,Medicine ,business - Abstract
12009 Background: Older adults are at risk for physical function decline during therapy for AML. Impaired physical function after induction therapy is associated with shorter survival Interventions designed to maintain function may improve treatment outcomes. We piloted a physical activity (PA) intervention among older adults receiving intensive chemotherapy for AML designed to prevent functional decline. Methods: Single institution randomized pilot study of PA vs. usual care. Eligibility included age ≥60 years, newly-diagnosed AML, ambulatory, planned intensive induction chemotherapy. Intervention participants were offered a PA session five days/week tailored daily to symptoms and conditions during the induction hospitalization. Session options were: 1) Standard (ward-based), walking + balance trahining + resistance exercises; 2) Intermediate (room-based), upper-body ergometer + balance training + resistance exercises; 3) Low-intensity (bed-based), upper-body ergometer + resistance exercises. Behavioral counseling sessions to establish PA goals and overcome barriers were conducted weekly during hospitalization and continued monthly by phone for 6 months. Assessment of physical function occurred at baseline, weekly during hospitalization (approximately 4-6 weeks), 3 months, and 6 months. The primary functional outcome of interest was the Short Physical Performance Battery (SPPB; 5 repeat chair stands, gait speed, balance tests; score 0-12 higher indicates better function). Clinically significant change in physical function was defined as ≥1.0 on the SPPB. Proportions of those that declined, remained stable, or improved on the SPPB were compared by group using an exact test for trend. Results: Among 96 eligible patients 70 enrolled (recruitment rate 73%, average participation 3 sessions/week). The mean age was 72.1±6.3 years, 70% were male. Mean baseline SPPB score was 7.0±3.8. In the surviving intention to treat population (N = 66), more intervention participants, compared to controls, maintained or improved their SPPB score (38% vs. 25%) during induction hospitalization (p = 0.278). Among those who achieved remission (N = 42), function was maintained or improved in a greater proportion of intervention participants (55%) compared to controls (23%), p = 0.047. Maintenance or improvement in SPPB from baseline to last follow-up (3 or 6 months post enrollment) was 62% vs 54% for intervention versus control among the intention to treat cohort (N = 50) and 67% vs. 55% among those who achieved remission (N = 40). Conclusions: A symptom adapted PA intervention with behavioral counseling during induction chemotherapy shows promise in preventing clinically meaningful decline in physical function among older adults with AML who achieve remission. Continued maintenance intervention may sustain benefits. Clinical trial information: NCT01519596.
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- 2021
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25. Efficacy of 10-day decitabine in acute myeloid leukemia
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Dianna S. Howard, Vivek Mehta, Susan Lyerly, Bayard L. Powell, Timothy S. Pardee, Ian M. Bouligny, Scott Isom, Sarah Dralle, Megan Manuel, Leslie R. Ellis, and Rupali Bhave
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Adult ,Male ,Oncology ,Cancer Research ,medicine.medical_specialty ,Time Factors ,Decitabine ,Disease-Free Survival ,Article ,03 medical and health sciences ,0302 clinical medicine ,Refractory ,Internal medicine ,Overall survival ,Humans ,Medicine ,Aged ,Aged, 80 and over ,Adult patients ,business.industry ,Cytogenetics ,Myeloid leukemia ,Hematology ,Middle Aged ,Survival Rate ,Leukemia, Myeloid, Acute ,Regimen ,030220 oncology & carcinogenesis ,Cohort ,Female ,business ,030215 immunology ,medicine.drug - Abstract
The azanucleotide decitabine is used in the treatment of acute myeloid leukemia (AML). Studies have shown conflicting results with 10-day regimens used in previously untreated AML patients. Additionally, there is little data on 10-day decitabine regimens in the relapsed setting. This study investigated outcomes of 108 adult patients with AML in the upfront and relapsed setting treated with a 10-day decitabine regimen. In the upfront group, the overall response rate (ORR, CR + CRi) was 36.1% and the median overall survival (OS) was 6.6 months, while the relapsed/refractory group had an ORR of 25% with an OS of 4.8 months. When analyzed with respect to cytogenetics, the upfront group featured an ORR of 28.1% with an OS of 9.4 months in the intermediate cytogenetic cohort compared to a 40.5% ORR and an OS of 5.4 months in the unfavorable cytogenetic cohort. An analysis of the relapsed/refractory group demonstrated an ORR of 26.3% with an OS of 7.9 months for intermediate cytogenetics versus 25.0% with an OS of 1.8 months in the unfavorable cohort. While these response rates are similar to previously published data, the median OS appears shorter.
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- 2021
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26. The Unified Approach to Treatment Center and CIBMTR Supports More Complete Information to Advance Therapies
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Alper Sayiner, Kent Kirimli, Dianna S. Howard, Garland Kitts, Lynn Fischer, and Tracy Coyne
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Transplantation ,Treatment center ,medicine.medical_specialty ,Complete information ,Computer science ,medicine ,Molecular Medicine ,Immunology and Allergy ,Medical physics ,Cell Biology ,Hematology - Published
- 2021
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27. Development and Implementation of Outpatient CAR-T Program at the Wake Forest Baptist Comprehensive Cancer Center
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Melanie Hooker, Mary B Seegars, Tracy Coyne, Dianna S. Howard, LeAnne Kennedy, Cesar Rodriguez, Rebecca Damron, Michelle Payne, David D. Hurd, and Rakhee Vaidya
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Transplantation ,business.industry ,medicine ,Molecular Medicine ,Immunology and Allergy ,Cancer ,Center (algebra and category theory) ,Cell Biology ,Hematology ,Medical emergency ,Car t cells ,medicine.disease ,business - Published
- 2021
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28. Development of a CAR-T Program from Inception to Implementation: Moving from a Novice to an Expert
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LeAnne Kennedy, Rakhee Vaidya, Mary B Seegars, Rebecca Damron, Dianna S. Howard, and Tracy Coyne
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Transplantation ,Engineering ,Aeronautics ,business.industry ,Molecular Medicine ,Immunology and Allergy ,Cell Biology ,Hematology ,Car t cells ,business - Published
- 2021
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29. Letermovir Prophylaxis and the Effect on Cytomegalovirus (CMV) Infection
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Brandi Anders, LeAnne Kennedy, Alyssa Bradshaw, and Dianna S. Howard
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Transplantation ,Letermovir ,business.industry ,Congenital cytomegalovirus infection ,Molecular Medicine ,Immunology and Allergy ,Medicine ,Cell Biology ,Hematology ,business ,medicine.disease ,Virology ,medicine.drug - Published
- 2021
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30. BEAM Conditioning for ASCT in High-Risk Geriatric Patients
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LeAnne Kennedy, Mary B Seegars, Dianna S. Howard, Brandi Anders, Anne Wofford, Scott Isom, and Elizabeth Rogers
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Transplantation ,medicine.medical_specialty ,business.industry ,medicine ,Molecular Medicine ,Immunology and Allergy ,Conditioning ,Cell Biology ,Hematology ,Radiology ,business ,Beam (structure) - Published
- 2021
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31. Final outcomes of escalated melphalan 280 mg/m
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Parameswaran, Hari, Donna E, Reece, Jasleen, Randhawa, Neal, Flomenberg, Dianna S, Howard, Ashrof Z, Badros, Aaron P, Rapoport, Barry R, Meisenberg, Joanne, Filicko-Ohara, Gordon L, Phillips, and David H, Vesole
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Adult ,Male ,Transplantation Conditioning ,Dose-Response Relationship, Drug ,Maximum Tolerated Dose ,Remission Induction ,Hematopoietic Stem Cell Transplantation ,Middle Aged ,Transplantation, Autologous ,Disease-Free Survival ,Amifostine ,Treatment Outcome ,Cytoprotection ,Humans ,Female ,Prospective Studies ,Multiple Myeloma ,Melphalan ,Aged - Abstract
The most common preparative regimen for autologous transplantation (ASCT) in myeloma (MM) consists of melphalan 200 mg/m
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- 2018
32. Informed Consent for Chemotherapy: ASCO Member Resources
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Courtney D. Storm, Dianna S. Howard, Michael M. Neuss, Hans W. Grünwald, Kristen K. McNiff, and Jacqueline Casillas
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medicine.medical_specialty ,Joint working ,Oncology (nursing) ,business.industry ,Health Policy ,Consent to treatment ,MEDLINE ,humanities ,Documentation ,Oncology ,Informed consent ,Family medicine ,Malpractice ,medicine ,Focus on Quality ,Quality of care ,business - Abstract
Consent to treatment is an important part of the delivery of quality cancer care. Physician practices that participate in ASCO’s Quality Oncology Practice Initiative (QOPI) and others expressed interest in having ASCO provide informed consent resources, and indicated that they would be more likely to use a consent form for chemotherapy if ASCO provided a template. Recent Journal of Oncology Practice articles outlining unique factors in consent for chemotherapy, documentation issues, and malpractice concerns also raised member interest. In response, members of ASCO’s Ethics and Quality of Care Committees formed a joint working group to design a consent form template and other resources that provide a framework for consent conversations between oncologists and patients receiving chemotherapy.
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- 2018
33. A Retrospective Validation of Three Standard Prognostic Instruments Used to Inform Decisions Regarding Autologous and Allogeneic Stem Cell Transplantation
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Cesar Rodriguez, Tracy Coyne, Dianna S. Howard, Michael McGown, Peggy Trotter, Zanetta S. Lamar, Mary B Seegars, Rakhee Vaidya, Emily V. Dressler, and Zachariah A. McIver
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Oncology ,Transplantation ,Validation study ,medicine.medical_specialty ,education.field_of_study ,business.industry ,Population ,Significant difference ,Hematology ,Transplant-Related Mortality ,Pulmonary function testing ,03 medical and health sciences ,surgical procedures, operative ,0302 clinical medicine ,hemic and lymphatic diseases ,030220 oncology & carcinogenesis ,Internal medicine ,medicine ,Stem cell ,business ,education ,Comorbidity index ,030215 immunology - Abstract
Background The Hematopoietic Cell Transplantation (HCT) – Specific Comorbidity Index (HCT-CI) measures the risk of transplant related mortality and predicts overall survival (OS) based on co-morbidities. In a prospective validation study of the HCT-CI by the Center for International Blood and Marrow Transplant Research (CIBMTR), HCT-CI ≥ 3 was associated with lower OS in both allogeneic (allo) and autologous (auto) HCT regardless of diagnoses, age, or conditioning. In contrast to the patients (pts) analyzed in the CIBMTR study, pts transplanted at Wake Forest more often have HCT ≥3. Methods We retrospectively analyzed data from pts transplanted from Sep 2014 to Sep 2016. 2-yr OS was observed for all pts. Results from 3 tools were used to compare predicted vs observed OS: HCT-CI, Disease Risk Index (DRI), and the CIBMTR survival calculator. Results Over 2 yrs, 216 pts were transplanted – 132 auto, median age 62 (26-78) and 84 allo, median age 55.5 (16-74). 59% of pts had a HCT-CI ≥3. In both groups, predicted and observed OS were not statistically different for those with HCT-CI 0. In contrast, predicted and observed OS for HCT-CI ≥3 were significantly different (p Conclusions Compared to the dataset utilized by the CIBMTR for validation of the HCT-CI, scores ≥ 3, largely accounted for by poor pulmonary function, are over represented in our population. Further analysis will need to be done to determine if the regional prevalence of poor pulmonary function is contributing to a significant difference in the predicted vs observed OS in our allo pts.
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- 2019
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34. Genetics of CD33 in Alzheimer's disease and acute myeloid leukemia
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Paul K. Crane, Christopher Medway, Shobha Potluri, Joe Chiles, James F. Simpson, Shubhabrata Mukherjee, Ying Liang, Christian M. Paumi, Dianna S. Howard, Steven G. Younkin, David W. Fardo, Steven Estus, Hualin S. Xi, and Manasi Malik
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Male ,Linkage disequilibrium ,Myeloid ,Genotype ,RNA Stability ,Sialic Acid Binding Ig-like Lectin 3 ,CD33 ,Gene Expression ,Single-nucleotide polymorphism ,Biology ,Antibodies, Monoclonal, Humanized ,Polymorphism, Single Nucleotide ,Lintuzumab ,Cell Line ,Exon ,Alzheimer Disease ,Genetics ,medicine ,Humans ,Genetic Predisposition to Disease ,RNA, Messenger ,Molecular Biology ,Alleles ,Genetic Association Studies ,Genetics (clinical) ,Aged ,Aged, 80 and over ,Association Studies Articles ,Myeloid leukemia ,Exons ,General Medicine ,medicine.disease ,Introns ,Alternative Splicing ,Leukemia, Myeloid, Acute ,Leukemia ,medicine.anatomical_structure ,Immunology ,Cancer research ,Female ,medicine.drug - Abstract
The CD33 single-nucleotide polymorphism (SNP) rs3865444 has been associated with the risk of Alzheimer's disease (AD). Rs3865444 is in linkage disequilibrium with rs12459419 which has been associated with efficacy of an acute myeloid leukemia (AML) chemotherapeutic agent based on a CD33 antibody. We seek to evaluate the extent to which CD33 genetics in AD and AML can inform one another and advance human disease therapy. We have previously shown that these SNPs are associated with skipping of CD33 exon 2 in brain mRNA. Here, we report that these CD33 SNPs are associated with exon 2 skipping in leukocytes from AML patients and with a novel CD33 splice variant that retains CD33 intron 1. Each copy of the minor rs12459419T allele decreases prototypic full-length CD33 expression by ∼ 25% and decreases the AD odds ratio by ∼ 0.10. These results suggest that CD33 antagonists may be useful in reducing AD risk. CD33 inhibitors may include humanized CD33 antibodies such as lintuzumab which was safe but ineffective in AML clinical trials. Here, we report that lintuzumab downregulates cell-surface CD33 by 80% in phorbol-ester differentiated U937 cells, at concentrations as low as 10 ng/ml. Overall, we propose a model wherein a modest effect on RNA splicing is sufficient to mediate the CD33 association with AD risk and suggest the potential for an anti-CD33 antibody as an AD-relevant pharmacologic agent.
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- 2015
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35. Outcomes and changes in code status of patients with acute myeloid leukemia undergoing induction chemotherapy who were transferred to the intensive care unit
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Bayard L. Powell, Timothy S. Pardee, Tamjeed Ahmed, Dmitriy Berenzon, Abby L. Koch, Jonathan M. Bishop, Scott Isom, Leslie R. Ellis, Dianna S. Howard, Susan Lyerly, and Heidi D. Klepin
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Adult ,Male ,Patient Transfer ,Cancer Research ,medicine.medical_specialty ,medicine.medical_treatment ,Kaplan-Meier Estimate ,law.invention ,03 medical and health sciences ,0302 clinical medicine ,law ,Internal medicine ,medicine ,Humans ,Aged ,Resuscitation Orders ,Retrospective Studies ,Mechanical ventilation ,Aged, 80 and over ,business.industry ,Septic shock ,Do not resuscitate ,Induction chemotherapy ,Hematology ,Induction Chemotherapy ,Middle Aged ,medicine.disease ,Intensive care unit ,Surgery ,Intensive Care Units ,Leukemia, Myeloid, Acute ,Oncology ,Respiratory failure ,030220 oncology & carcinogenesis ,Cohort ,Female ,Hemodialysis ,business ,030215 immunology - Abstract
Patients with Acute Myeloid Leukemia (AML) have compromised marrow function and chemotherapy causes further suppression. As a result complications are frequent, and patients may require admission to the intensive care unit (ICU). How codes status changes when these events occur and how those changes influence outcome are largely unknown. Outcomes for adult patients with AML, undergoing induction chemotherapy, and transferred to the ICU between January 2000 and December 2013 were analyzed. 94 patients were included. Median survival was 1.3 months. At 3 and 6 months overall survival (OS) was 27% and 18% respectively. Respiratory failure was the most common reason for transfer to ICU (88%), with 63% requiring mechanical ventilation at transfer. Other reasons included: cardiac arrest (18%), septic shock (17%), hypotension (9%), and acute renal failure (9%). The most frequent interventions were mechanical ventilation in 85%, vasopressors in 62%, and hemodialysis in 30%. Following transfer 55 patients (58%) had a change in code status. Overall, 46 patients (49%) changed from Full Code (FC) to Comfort Care (CC), 7 (7%) from FC to Do Not Resuscitate (DNR), and 2 (2%) from DNR to CC. For the entire cohort, ICU mortality (IM) was 61% and hospital mortality (HM) was 71%. For FC or DNR patients, IM was 30% and HM was 41%. For CC patients, IM was 90% and HM was 100%. Overall, 27 patients (29%) survived to discharge. Of those discharged, 22 (81%) were alive at 3 months and 17 (63%) were alive at 6 months. In conclusion, patients that required ICU admission during induction chemotherapy have a poor prognosis. Code status changed during the ICU stay for the majority of patients and always to a less aggressive status.
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- 2017
36. A Phase 2 study of bortezomib combined with either idarubicin/cytarabine or cytarabine/etoposide in children with relapsed, refractory or secondary acute myeloid leukemia: A report from the Children's Oncology Group
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Jennifer J. Ballard, Alan S. Gamis, Gaye Jenkins, Franklin O. Smith, Gerrit Jan Schuurhuis, Terzah M. Horton, John P. Perentesis, Dianna S. Howard, Jeffrey A. Moscow, Todd A. Alonzo, Robert B. Gerbing, Angèle Kelder, and Kathleen Adlard
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Oncology ,medicine.medical_specialty ,Chemotherapy ,business.industry ,Bortezomib ,medicine.medical_treatment ,Cytarabine/Etoposide ,Hematology ,medicine.disease ,Leukemia ,Tolerability ,hemic and lymphatic diseases ,Internal medicine ,Pediatrics, Perinatology and Child Health ,medicine ,Cytarabine ,Secondary Acute Myeloid Leukemia ,Idarubicin ,business ,neoplasms ,medicine.drug - Abstract
Background This Phase 2 study tested the tolerability and efficacy of bortezomib combined with reinduction chemotherapy for pediatric patients with relapsed, refractory or secondary acute myeloid leukemia (AML). Correlative studies measured putative AML leukemia initiating cells (AML-LIC) before and after treatment.
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- 2014
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37. Selinexor in Combination with Induction and Consolidation Therapy in Older Adults with AML Is Highly Active
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Bayard L. Powell, Susan Lyerly, Dianna S. Howard, Emanuel F. Petricoin, Kevin H. Lin, Mariaelena Pierobon, Kris C. Wood, Rupali Bhave, Leslie R. Ellis, Megan Manuel, Justine C. Rutter, Sarah Dralle, and Timothy S. Pardee
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Oncology ,medicine.medical_specialty ,Daunorubicin ,business.industry ,Immunology ,Cancer ,Cell Biology ,Hematology ,medicine.disease ,Biochemistry ,Chemotherapy regimen ,Consolidation therapy ,Transplantation ,Leukemia ,Internal medicine ,medicine ,Cytarabine ,Adverse effect ,business ,medicine.drug - Abstract
Background: Acute myeloid leukemia (AML) is an aggressive myeloid cancer of the hematopoietic system that primarily affects older adults and is characterized by therapy resistance and dismal outcomes. Novel approaches to treat AML are desperately needed. Selinexor is a small-molecule inhibitor of the nuclear export protein XPO1. Treatment of AML cells with selinexor was shown to sensitize them to chemotherapy in part by blocking the nuclear export of topoisomerase II, resulting in increased DNA strand breaks when an anthracycline is present. Furthermore, selinexor has shown encouraging results when combined with chemotherapy in the relapsed setting. This abstract reports on the initial results of a randomized phase II study of induction and consolidation with or without selinexor in newly diagnosed patients with AML 60 years of age or older. Methods: Patients 60 years of age or older with newly diagnosed de novo AML were randomized between 7+3 or 7+3+selinexor induction. Responding patients could then go on to high dose cytarabine consolidation with or without selinexor as per their initial treatment assignment. Patients in the selinexor arm who completed all planned consolidation could then move to maintenance therapy with selinexor alone. During induction cytarabine was dosed at 100 mg/m2 by continuous infusion for 7 days and daunorubicin was dosed at 60 mg/m2 on days 1-3. In consolidation cytarabine was dosed at 1.5 gm/m2 given Q12 hours on days 1, 3 and 5. Selinexor was dosed at 60 mg PO on days 1, 3, 8, 10, 15 and 17 during induction and consolidation and on days 1 and 8 every 21 days in maintenance. Optional blood samples were collected just prior to and at several time points after selinexor during induction. Mononuclear cells were isolated from these samples, lysed and lysates evaluated for protein pathway drug target activation mapping by reverse phase phosphoprotein array (RPPA). Results: Thirteen patients have been enrolled to date with 12 available for evaluation. Of the 12 evaluable patients 6 were randomized to each arm. Baseline demographics are listed in Table 1. Overall the combination was well tolerated with no patients discontinuing selinexor secondary to treatment related adverse events. In the standard arm 3 of 6 patients achieved a complete remission. Of the 3 responders 1 has relapsed, 1 has gone on to transplant and one has completed consolidation chemotherapy. In the selinexor arm 5 of 6 patients achieved a complete remission and 1 patient achieved a morphologic leukemia free state. All patients given selinexor achieved a response. Of the 5 responders 3 have gone on to transplant, 1 is on maintenance therapy (completed 14 cycles) and one is completing consolidation therapy. In the standard arm no patients died during induction and 3 of 6 patients have died from progressive disease. In the selinexor arm 1 patient died during induction and none of the remaining patients have progressed (Figure 1 and Table 2). No difference in the AE profile was noted between arms and no unexpected side effects were observed. The patient on long term maintenance selinexor is tolerating it without significant AEs to date. Blood samples were available from 3 patients from the selinexor arm. RPPA based protein pathway activation mapping analysis of PBMCs revealed a significant increase in phosphorylation of AMPK, BAD and LC3B at one-hour post treatment that returned to baseline by 2 hours suggesting a transient increase in these pathways that was subsequently suppressed (Figure 2). Conclusions: Selinexor in combination with standard induction and consolidation therapy appears highly active in older de novo AML patients. Selinexor may increase response by modulation of AMPK, autophagy and BAD phosphorylation. Enrollment is ongoing. Disclosures Pardee: Spherix Intellectual Property: Research Funding; CBM Bipharma: Membership on an entity's Board of Directors or advisory committees; Amgen: Speakers Bureau; Celgene: Speakers Bureau; Pharmacyclics/Janssen: Speakers Bureau; Karyopharm: Research Funding; Rafael Pharmaceuticals: Consultancy, Research Funding. Manuel:Novartis: Speakers Bureau; Jazz Pharmaceuticals: Speakers Bureau. Powell:Pfizer: Consultancy, Research Funding; Rafael Pharmaceuticals: Consultancy, Research Funding; Novartis: Consultancy, Speakers Bureau; Jazz Pharmaceuticals: Consultancy, Research Funding, Speakers Bureau; Janssen: Research Funding. OffLabel Disclosure: Selinexor is not approved for the treatment of AML
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- 2019
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38. Assessing Efficacy and Safety of Daunorubicin and Cytarabine Liposomal in Patients with Acute Myeloid Leukemia
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Timothy S. Pardee, Bayard L. Powell, Sarah Dralle, Megan Manuel, Susan Lyerly, Maho Hibino, Leslie R. Ellis, Rebecca Garcia Hunt, Dianna S. Howard, Elizabeth Rogers, and Rupali Bhave
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Oncology ,medicine.medical_specialty ,business.industry ,Daunorubicin ,medicine.medical_treatment ,Immunology ,Preleukemia ,Myeloid leukemia ,Cell Biology ,Hematology ,Biochemistry ,Transplantation ,hemic and lymphatic diseases ,Internal medicine ,Absolute neutrophil count ,Cytarabine ,Medicine ,business ,Adverse effect ,Neoadjuvant therapy ,medicine.drug - Abstract
Background. Acute myeloid leukemia (AML) is the most common acute leukemia in adults. The median age of diagnosis is 67 years old, and it has unfavorable outcomes in older patients. Approximately one-third of patients are diagnosed after the age of 75. Thus, as the population continues to increase in age, the incidence of AML will continue to expand (NCCN guidelines: AML. Version 3.2019). The long term disease free survival (DFS) rates for patients > 60 years of age is 5-15% whereas younger patients < 60 years of age have a better DFS rate of up to 40% (Dohner H, et al. N Engl J Med. 2015). Recent advancements have been made in patients with AML, including the approval of daunorubicin and cytarabine liposomal (Vyxeos®) for the treatment of adults with 2 poor risk types of AML: newly diagnosed therapy related AML (t-AML) or AML with myelodysplasia-related changes (AML-MRC). Given the financial constraints of this new medication, our objective was to determine the safety and efficacy of daunorubicin and cytarabine liposomal in our adult patients with t-AML and AML-MRC at a single academic medical center. Methods. This was a single center, retrospective, chart review at Wake Forest Baptist Health (WFBH) Comprehensive Cancer Center from August 1, 2017 to November 1, 2018. Patients were selected via report generation if they had received at least one dose of daunorubicin and cytarabine liposomal during the study period. The initial induction dose of daunorubicin and cytarabine liposomal was 44 mg/m2 of daunorubicin and 100 mg/m2 cytarabine administered on days 1, 3, and 5 for up to 2 cycles to achieve remission. If a second induction was necessary, the same induction doses were given on days 1 and 3 only. The consolidation dose was 29 mg/m2 of daunorubicin and 65 mg/m2 of cytarabine on days 1 and 3 for up to 2 cycles. The primary endpoint was overall survival (OS). Secondary endpoints included event free survival (EFS), 30-day and 60-day mortality, complete remission (CR) and morphologic complete remission with incomplete blood count recovery (CRi), adverse drug reactions, and financial impact to the health system. Descriptive statistics were utilized for demographic data. Time to event data was analyzed using the Kaplan-Meier method. SPSS IBM and Microsoft Excel Software were utilized for data analysis. Results. A total of 37 AML patients were identified as receiving daunorubicin and cytarabine liposomal from August 2017 to November 2018. Of those 37 patients, 27 had AML-MRC and 10 had t-AML. The average patient was a 70 year old Caucasian male with an ECOG performance status of 1 and a Charlson Comorbidity Index of 6 (Table 1). The median OS was 10 months and EFS was 7 months. The 30-day mortality rate was 16% and 60-day mortality rate was 19%. Eighteen patients (49%) achieved a CR and 2 patients (5%) achieved a CRi. A subgroup analysis was conducted for prior hypomethylating agent (HMA) use, age > 75 years old, < 60 years old, molecular mutations including FLT3-ITD and TP53 mutations, and t-AML. Poorer outcomes were noted in patients > age 75, prior HMA use, and the t-AML subgroups. Table 3 highlights the OS, 60-day mortality rate, transplant received and CR+CRi for each subgroup. The median time to platelet and absolute neutrophil count (ANC) recovery was 32 and 33 days, respectively. Eight patients (21.6%) proceeded to transplant post administration of daunorubicin and cytarabine liposomal. All patients experienced at least one adverse event with hematologic being the most commonly observed toxicity (Table 4). Most patients received induction therapy with daunorubicin and cytarabine liposomal in the inpatient setting whereas consolidation was predominantly administered in an outpatient encounter. Conclusions. Daunorubicin and cytarabine liposomal was considered an effective treatment option for patients with t-AML and AML-MRC with a CR+CRi rate of 54%. Younger patients (< 60 years old) exhibited the greatest benefit with an OS of 12 months and 60 day mortality rate of 0%. However, poorer outcomes were demonstrated in elderly patients (> 75 years old), patients with FLT3-ITD positive mutations, and patients with previous HMA use, with an OS less than 2 months in each subgroup and mortality rates ranging up to 60%. Thus, additional studies are necessary to determine the role of daunorubicin and cytarabine liposomal in these higher risk patient subgroups > age 75, FLT3-ITD positive patients, and patients with previous HMA use. Disclosures Manuel: Novartis: Speakers Bureau; Jazz Pharmaceuticals: Speakers Bureau. Pardee:Rafael Pharmaceuticals: Consultancy, Research Funding; Karyopharm: Research Funding; Spherix Intellectual Property: Research Funding; Pharmacyclics/Janssen: Speakers Bureau; Celgene: Speakers Bureau; Amgen: Speakers Bureau; CBM Bipharma: Membership on an entity's Board of Directors or advisory committees. Powell:Janssen: Research Funding; Rafael Pharmaceuticals: Consultancy, Research Funding; Novartis: Consultancy, Speakers Bureau; Jazz Pharmaceuticals: Consultancy, Research Funding, Speakers Bureau; Pfizer: Consultancy, Research Funding.
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- 2019
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39. Evaluating the Utilization of All-Trans Retinoic Acid and Arsenic Trioxide during Consolidation Therapy for Patients Receiving Treatment for Acute Promyelocytic Leukemia
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Rebecca Garcia Hunt, Maho Hibino, Timothy S. Pardee, Susan Lyerly, Bayard L. Powell, Sarah Dralle, Rupali Bhave, Leslie R. Ellis, Megan Manuel, Dianna S. Howard, and Laura A Bowers
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Acute promyelocytic leukemia ,Oncology ,medicine.medical_specialty ,Surrogate endpoint ,business.industry ,Immunology ,Retinoic acid ,Cell Biology ,Hematology ,medicine.disease ,Biochemistry ,symbols.namesake ,chemistry.chemical_compound ,Peripheral neuropathy ,chemistry ,Tretinoin ,Internal medicine ,medicine ,symbols ,Arsenic trioxide ,business ,Adverse effect ,neoplasms ,Fisher's exact test ,medicine.drug - Abstract
Background. Acute promyelocytic leukemia (APL) is a subtype of acute myeloid leukemia (AML) accounting for approximately 10% of AML cases. Advancements in the management of APL have led to complete remission (CR) rates of 90-100% and 5-year overall survival (OS) rates between 86-97%. Standard treatment of APL consists of induction and consolidation, with or without post-consolidation therapy, which is directed by risk group, age, and cardiovascular risk. A standard consolidation option consists of arsenic trioxide (ATO) and all-trans retinoic acid (ATRA) (NCCN Guidelines, AML Version 3.2019). Frequently patients are unable to obtain consolidation with ATRA due to the high prescription co-pay and limited financial assistance. This study assessed the efficacy, safety, and financial impact of APL consolidation therapy with ATRA/ATO compared to ATO monotherapy at a single institution. Methods. This single-center, retrospective, chart-review study assessed adult patients with APL who received ATRA/ATO induction, followed by consolidation with ATRA/ATO or ATO monotherapy between November 2012 to January 2018. The primary efficacy endpoint was OS. Secondary endpoints included event-free survival (EFS), relapse-free survival (RFS), hematologic CR or molecular CR (CRm), incidence of adverse drug events, and outpatient accessibility of ATRA. Numerical data were expressed as medians and interquartile range (IQR) and categorical data were evaluated using the Fisher Exact test. The Log-rank test was used for time to event data and analyzed using the Kaplan-Meier method. A P-value of < 0.05 was defined as statistically significant. Results. The final analysis included 31 patients, 25 patients received standard ATRA/ATO and 6 patients received ATO monotherapy. Patients in the ATRA/ATO group had a median age of 47 years (range 19 - 72); 8 had low risk and 15 had intermediate risk APL. Patients in the ATO monotherapy group had a median age of 73 years (range 70 - 83); 4 had low risk and 1 had intermediate risk APL. Patients in the ATO monotherapy group had more comorbidities, with all patients having a Charlson Comorbidity Index of 4 or higher compared to only 44% of the ATRA/ATO group (p=0.02). A dose reduction for ATO was required for 50% and 28% of patients in the ATO monotherapy and ATRA/ATO groups, respectively due to peripheral neuropathy. During consolidation, patients in the ATO monotherapy group received a median of 5.4 mg/kg of ATO over 2 cycles compared to 11.6 mg/kg over 4 cycles in the ATRA/ATO group (Table 1). Five of six patients (83.3%) and 24 of 25 patients (96%) were alive at last follow-up in the ATO monotherapy and ATRA/ATO groups with a median follow-up of 33.3 months and 35.5 months, respectively (Graph 1). Secondary endpoints are provided in Table 2. There was 1 death in each group, both due to unknown causes. All adverse events occurred in a higher proportion of patients in the ATRA/ATO group (Graph 2). The incidence of headache was significantly higher in the ATRA/ATO group, occurring in 68% of patients and leading to ATRA discontinuation for 1 patient (Table 3), compared to 0 events in the ATO monotherapy group (p=0.004). Barriers to access occurred in 19.4% (6 of 31) of all patients. In addition to the 4 patients who required omission of ATRA upfront due to cost, 2 additional patients discontinued ATRA during consolidation due to affordability (Table 3). Conclusions. Patients in the ATO monotherapy group were on average older, had more comorbid conditions, and received a lower cumulative dose of ATO during consolidation. The standard dose of ATO during consolidation is 12 mg/kg administered over 4 cycles. In our study, patients in the ATO monotherapy group received a median of 5.4 mg/kg of ATO over 2 cycles compared to 11.6 mg/kg over 4 cycles in the ATRA/ATO group. Despite discrepancies in age, comorbidities, and total dose of ATO received, outcomes were similar in the ATRA/ATO and ATO monotherapy groups. Although limited by a small sample size and retrospective design, this study suggests that elimination of ATRA from consolidation may be an acceptable option for patients that are unable to obtain ATRA or that experience intolerable side effects. These findings also suggest that lower cumulative doses of ATO during consolidation may produce similar efficacy with lesser toxicity. Future large, multicenter studies are necessary to confirm the efficacy and safety of these findings. Table Disclosures Manuel: Novartis: Speakers Bureau; Jazz Pharmaceuticals: Speakers Bureau. Pardee:Rafael Pharmaceuticals: Consultancy, Research Funding; Karyopharm: Research Funding; Pharmacyclics/Janssen: Speakers Bureau; Celgene: Speakers Bureau; Amgen: Speakers Bureau; CBM Bipharma: Membership on an entity's Board of Directors or advisory committees; Spherix Intellectual Property: Research Funding. Powell:Rafael Pharmaceuticals: Consultancy, Research Funding; Novartis: Consultancy, Speakers Bureau; Jazz Pharmaceuticals: Consultancy, Research Funding, Speakers Bureau; Pfizer: Consultancy, Research Funding; Janssen: Research Funding.
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- 2019
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40. Efficacy and Cost Savings Associated with a Conversion from Filgrastim to Filgrastim-Sndz in Stem Cell Transplant Patients Undergoing Mobilization
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LeAnne Kennedy, Brandi Anders, Lauren Dawn Curry, and Dianna S. Howard
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Transplantation ,medicine.medical_specialty ,Mobilization ,business.industry ,Biosimilar ,Hematology ,Filgrastim ,medicine.disease ,Autologous stem-cell transplantation ,Apheresis ,Internal medicine ,Medicine ,Stem cell ,business ,Multiple myeloma ,Cohort study ,medicine.drug - Abstract
In patients undergoing autologous stem cell transplantation (aSCT), the recombinant human granulocyte colony-stimulating factor, filgrastim, has been historically utilized during mobilization. Filgrastim-SNDZ, a biosimilar of filgrastim, received landmark approval as the first biosimilar product approved by the FDA in the United States. Biosimilar products offer cost benefit over the reference product, while maintaining similar efficacy. As a result of the recent approval, our medical center made the conversion from using filgrastim to filgrastim-SNDZ as the preferred mobilizing agent to provide patients the same benefits at a reduced cost. The primary objective of this retrospective, observational cohort study was to assess the efficacy of filgrastim-SNDZ as a mobilizing agent in the SCT patient population compared to the formerly used reference product, filgrastim. The secondary objective was to confirm the cost savings associated with the conversion from filgrastim to filgrastim-SNDZ. Data was collected on two cohorts of patients undergoing mobilization prior to an aSCT who received either filgrastim or filgrastim-SNDZ. Efficacy was assessed based of the number of days of stem cell apheresis and number of CD34 stem cells collected during apheresis in both cohorts. Cost savings were assessed based on cost difference (average wholesale price) between the drug products. In total, 186 patients received an aSCT during this time frame. Sixty-nine patients were included in the filgrastim group and 78 were included in the filgrastim-SNDZ group. The difference in number of CD34 cells collected was not significant (p = 0.17). The median number of CD34 cells collected was 7.24 × 106 in the filgrastim group and 8.245 × 106 in the filgrastim-SNDZ group. The filgrastim-SNDZ group had a larger range of CD34 cells collected during apheresis than the filgrastim group. There was no statistically significant difference in number of CD34 cells collected between the groups in patients with multiple myeloma (p = 0.0969) or with non-Hodgkin's lymphoma (p = 0.976). Number of CD34 cells collected was also tested for non-inferiority with a non-inferiority margin of 0.73 (10%) and filgrastim-SNDZ was shown to be non-inferior in this outcome to filgrastim. The median number of days of apheresis was 2 in both groups and there was no significant difference in this outcome between the groups (p = 0.36). The cost comparison between groups showed significant cost savings with filgrastim-SNDZ. Annual cost savings is projected to be $92,000 for 93 patients receiving an average of 5 doses of filgrastim-SNDZ. This study shows that using filgrastim-SNDZ is an effective and cost savings option for mobilization prior to aSCT.
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- 2019
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41. Factors Affecting the Survival of Therapy Related AML/MDS, Secondary AML and De Novo AML
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Bayard L. Powell, Rao Mushtaq, Scott Isom, Dianna S. Howard, Isra'a Khan, Faisal Akbar, and Timothy S. Pardee
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medicine.medical_specialty ,Therapy related ,business.industry ,Proportional hazards model ,Incidence (epidemiology) ,Immunology ,Hazard ratio ,Cell Biology ,Hematology ,Secondary AML ,Biochemistry ,Natural history of disease ,Internal medicine ,CEBPA ,Medicine ,Underweight ,medicine.symptom ,business - Abstract
Introduction: Patients exposed to cytotoxic agents are at a higher risk of developing therapy related AML and MDS (tAML/tMDS), and have poor survival as compared to de novo AML due to high risk of adverse features. Secondary AML (sAML)includes patients with progression from myeloproliferative neoplasms (MPN) and myelodysplastic syndrome (MDS) to AML, considering this progression could be natural history of disease process. Patients with tAML are considered to have an inferior outcome compared with de novo AML. In this retrospective chart review study, we aimed to look at factors affecting the survival of tAML/tMDS, sAML and de novo AML. Method: This retrospective analysis included 219 AML patients treated at Wake Forest Baptist Medical Center between January 2010 and December 2016. Kaplan-Meier estimation was used to evaluate survival at one and two-year period in these three types of AML. Multiple Cox proportional hazards models were used to examine the interaction between baseline characteristics (Table 1) and AML type (tAML/tMDS, sAML, de novo AML) on survival. Backward selection method was used to identify important predictors for a final model. Hazard ratios and 95% CI of all-cause mortality were based on the final Cox model. Results: We analyzed 219 patients with AML diagnosis. Of those 151 (69%) were de novo AML, 25 (11%) sAML and 43 (20%) tAML/tMDS, with mean age of 60.7, 70.7, and 69.7 years respectively. 88% of sAML and 72% of tAML/tMDS were ≥ 65 years compared to 50% of de novo AML patients (p=0.0009). More patients were in underweight/normal BMI (< 24.9) category of sAML (50%) compared to 36% of de novo AML and 21% of tAML/tMDS although this was not statistically significant (p=0.10). There were more females with tAML/tMDS (51%) compared to de novo AML (48%) and sAML (40%) (p=0.52). Most patients in all three groups of AML were white with 79% of de novo AML, 88% of sAML and 88% of tAML/tMDS. Almost one-third of sAML (33%) and tAML/tMDS (38%) were in adverse risk category group with 24% of de novo AML in this category. Most of de novo (62%), sAML (67%) and tAML/tMDS (45%) were in intermediate risk category. There were 5 patients with tAML/tMDS in favorable risk category with zero sAML and 18 de novo AML in this category. 54% of our patients had ECOG performance score of 0-1. A majority of sAML (63%) had a positive smoking history compared to 47% of de novo AML and 44% of tAML/tMDS. Majority of patients in the three categories denied any alcohol use. Incidence of FLT-3 mutation was 23% in de novo AML, 0% in sAML and 9% in tAML/tMDS (p=0.0001). NPM1 mutation was present in 19% of de novo AML, none of sAML and 5% in tAML/tMDS (p = 0.0016). CEBPa mutation was present in 6% of de novo AML, 4% of sAML and 2% of tAML/tMDS. Median survival was 18.5 months for de novo AML (95% CI 14.9- 23.7), 7.2 months for tAML/tMDS (95% CI 3.3- 11.5) and 7.0 months for sAML (95% CI 3.4-15.6). The median survival was longer among males, compared to females with de novo AML (23.2 months in males; 95% CI 18.3-37.1 vs. 14.6 months in females; 95% CI 10.3-19.0) compared to sAML (13.5 months in males; 95% CI 3.8-55 vs, 3.3 months in females; 95% CI 0.2-8.1) and tAML/tMDS (6.3 months in males; 95% CI 4.5-17.8 vs. 7.2 months in females; 95% CI 2.3-11.5) p=0.06. Patients with adverse risk category had a shorter median survival compared to those with favorable risk category, especially in tAML/tMDS but this was not significant. After adjusting for age, risk category and FLT-3 status, the type of AML was not a significant predictor of survival. However, when compared with de novo AML, patients with sAML and tAML/tMDS appear to have a somewhat increased risk of death (HR 1.3; 95% CI 0.7-2.4 and 1.6; 95% CI 0.9, 2.7 respectively). Mortality was 4.5 (95% CI 1.8, 11.3) and 9.3 (95% CI 3.6, 24.0) times higher in patients with intermediate and adverse risk category respectively, when compared to the favorable risk group. Patients with positive FLT-3 had 1.6 times mortality compared to negative FLT-3 (95% CI 1.0, 2.7). Conclusion: We found that median survival was better in de novo AML compared to sAML and tAML/tMDS. There was no difference in survival between sAML and tAML/tMDS. Advancing age increases the odds of death across three types of AML. It is important to note that the effect of patient characteristics on survival is mostly consistent across the AML types and that once the major survival predictors are accounted for, the type of AML is no longer significant. Disclosures Pardee: Amgen: Speakers Bureau; Karyopharm: Research Funding; Novartis: Speakers Bureau; Celgene: Speakers Bureau; Rafael Pharmaceuticals: Employment. Powell:Rafael Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees.
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- 2018
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42. Therapeutic Manipulation of Cancer Cell Metabolism with the Mitochondrial Metabolism Inhibitor Cpi-613 in Addition to Chemotherapy Abrogates the Adverse Prognostic Effect of Age in Relapsed and Refractory AML
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Timothy S. Pardee, Susan Lyerly, Megan Manuel, Rupali Bhave, Sarah Dralle, Leslie R. Ellis, Bayard L. Powell, Dianna S. Howard, and Scott Isom
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0301 basic medicine ,Oncology ,Asparaginase ,medicine.medical_specialty ,medicine.medical_treatment ,Immunology ,Biochemistry ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Refractory ,Internal medicine ,medicine ,Mitoxantrone ,Chemotherapy ,business.industry ,Cancer ,Cell Biology ,Hematology ,medicine.disease ,Chemotherapy regimen ,Clinical trial ,030104 developmental biology ,chemistry ,030220 oncology & carcinogenesis ,Cytarabine ,business ,medicine.drug - Abstract
Background: Acute myeloid leukemia is an aggressive malignancy with poor outcomes especially in patients 60 years of age or older. This thought to be in part from increased resistance to chemotherapy in AML cells arising in an older host. One of the nine recognized biological hallmarks of aging is a decline in mitochondrial quality. The effect of exploiting this age-related metabolic vulnerability in relapsed AML has not been previously established. CPI-613 is a first-in-class agent that inhibits pyruvate dehydrogenase and α-ketoglutarate dehydrogenase, effectively impairing the TCA cycle. We have combined CPI-613 with high dose cytarabine and mitoxantrone in phase I and II clinical trials in over 100 patients with relapsed or refractory AML. Methods: To determine the effect of the addition of CPI-613 in older patients, the phase I and II datasets were combined and outcomes by age were analyzed and compared to age related outcomes in a historical dataset of patients treated with a high dose cytarabine, mitoxantrone and L-asparaginase but without CPI-613. In both trials, patients were given CPI-613 as a 2-hour infusion on days 1 through 5. Cytarabine was dosed at 3,000 mg/m² (if younger than 60) or at 1,500 mg/m² (if 60 years of age or older), given every 12 hours for 5 doses, starting on day 3 following the CPI-613 infusion. The mitoxantrone was dosed at 6 mg/m² and is given once daily following the first, third and fifth cytarabine doses. At day 14, nadir marrow was evaluated, and patients with residual disease could be re-treated as above or with an abbreviated 3-day cycle. Responding patients were eligible to receive up to 2 abbreviated 3-day consolidation cycles. The historical cohort was treated identically without CPI-613, except L-Asparaginase was given at a dose of 6,000 units/m2 following the last dose of cytarabine. Results: Patient characteristics are summarized in Table 1. In the historical dataset younger patients had a highly significant increase in median overall survival when compared to patients ≥60 years of age (figure 1A). In contrast, older and younger patients treated with CPI-613 in addition to the chemotherapy had no significant difference in median survival (figure 1B). Additionally, when outcome by dose of CPI-613 was analyzed, older but not younger patients had a significant improvement in survival when given a dose of 2,000 mg/m2 compared to those given 1,500 mg/m2 (figure 1C+D). Patients 60 years of age or older had a response rate of 55% and a median overall survival of 12.4 months when treated with a dose of CPI-613 of 2,000 mg/m2. Conclusions: Targeting mitochondrial metabolism exploits an age-related metabolic vulnerability in AML arising in older patients. These results have led to a randomized phase III trial of CPI-613 at 2,000 mg/m2 in combination with high dose cytarabine and mitoxantrone compared to high dose cytarabine and mitoxantrone alone in relapsed or refractory AML patients 60 years of age or older. Disclosures Pardee: Amgen: Speakers Bureau; Karyopharm: Research Funding; Celgene: Speakers Bureau; Rafael Pharmaceuticals: Employment; Novartis: Speakers Bureau. Ellis:Alexion: Speakers Bureau. Powell:Rafael Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees.
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- 2018
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43. Is there a benefit of re-induction therapy in adult patients with AML with <20% blasts?
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Paz Vellanki, Susan Lyerly, Leslie R. Ellis, Timothy S. Pardee, Sarah Dralle, Kavya Kannan, Heidi D. Klepin, Allison Winter, Bayard L. Powell, Bernard Tawfik, Dianna S. Howard, Megan Manuel, Scott Isom, and Rupali Bhave
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Oncology ,Cancer Research ,medicine.medical_specialty ,Adult patients ,business.industry ,Induction chemotherapy ,Myeloid leukemia ,Newly diagnosed ,hemic and lymphatic diseases ,Internal medicine ,Induction therapy ,parasitic diseases ,medicine ,business - Abstract
7021Background: Decision on re-induction (RI) therapy in adult patients with newly diagnosed acute myeloid leukemia (AML) who have received induction chemotherapy (ICT) when there are less than 20%...
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- 2018
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44. Fatal Rhizopus Pneumonia in Allogeneic Stem Cell Transplant Patients Despite Posaconazole Prophylaxis: Two Cases and Review of the Literature
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Julie A. Ribes, Athanasios T. Skoutelis, Ioannis G. Baraboutis, Jeanette Prante, Amber Lawson, Lazaros J. Lekakis, Dianna S. Howard, Gregory J. Davis, and Gregory Monohan
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Male ,Mucorales ,Posaconazole ,medicine.medical_specialty ,Antifungal Agents ,Itraconazole ,GVHD ,Chemoprevention ,Myelogenous ,Fatal Outcome ,Internal medicine ,medicine ,Humans ,Mucormycosis ,Transplantation, Homologous ,Transplantation ,biology ,BMT ,business.industry ,Hematopoietic Stem Cell Transplantation ,Pneumonia ,Hematology ,Middle Aged ,Triazoles ,biology.organism_classification ,medicine.disease ,Leukemia ,Immunology ,business ,Rhizopus ,Fluconazole ,medicine.drug - Abstract
Posaconazole is a triazole with broad spectrum of activity against multiple fungi including members of the fungal order Mucorales. This activity has been shown both in clinical and in vitro studies, which are critically reviewed here. It has become very popular in prophylaxis in acute myelogenous leukemia (AML) induction and in the graft-versus-host disease (GVHD) settings after 2 recent prospective trials that showed advantage of posaconazole prophylaxis compared to fluconazole or itraconazole. In this report, 2 patients are presented, in whom, despite posaconazole prophylaxis, invasive and ultimately fatal Rhizopus pulmonary infections developed. These cases are similar to a previously reported case of Rhizopus infection in a stem cell transplant recipient who also received posaconazole, indicating a potential newly recognized pattern of breakthrough infections in patients receiving posaconazole prophylaxis.
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- 2009
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45. BK virus nephropathy after allogeneic stem cell transplantation: A case report and literature review
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Bonnie Mitchell, Dianna S. Howard, Ioannis G. Baraboutis, Lazaros J. Lekakis, and Valentina Macrinici
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Male ,Reoperation ,Hepatorenal Syndrome ,Transplantation Conditioning ,medicine.medical_treatment ,Graft vs Host Disease ,Hematopoietic stem cell transplantation ,medicine.disease_cause ,Antiviral Agents ,Transplantation, Autologous ,Tacrolimus ,Nephropathy ,chemistry.chemical_compound ,Fatal Outcome ,Postoperative Complications ,Cystitis ,medicine ,Humans ,Transplantation, Homologous ,Lymphoma, Follicular ,Polyomavirus Infections ,business.industry ,Hematopoietic Stem Cell Transplantation ,Immunoglobulins, Intravenous ,Hematology ,Middle Aged ,medicine.disease ,BK virus ,Transplantation ,surgical procedures, operative ,chemistry ,BK Virus ,Myelodysplastic Syndromes ,Cytomegalovirus Infections ,Immunology ,Kidney Failure, Chronic ,Nephritis, Interstitial ,Alemtuzumab ,business ,Immunosuppressive Agents ,medicine.drug ,Kidney disease ,Cidofovir - Abstract
Polyomaviruses are increasingly recognized as important human pathogens. Among those, BK virus has been identified as the main cause of polyomavirus-associated nephropathy (PVAN), a major cause of renal allograft failure. PVAN has also been well described in the setting of non-renal solid organ transplantation. The reports of PVAN after hematopoietic stem cell transplantation (HCT) are surprisingly very few. Here, we describe a patient with treatment-related myelodysplastic syndrome who received an unrelated donor HCT after ablative conditioning and in vivo T cell depletion with alemtuzumab. He developed a biopsy-proven BK nephropathy, which contributed to his renal failure. Leflunomide as well as cidofovir were given at different times, both in combination with intravenous immunoglobulin. Both treatments were effective in reducing the BK viral load, the cystitis symptoms and both stabilized but did not really improved the renal function. The patient was still dialysis-dependent when he died from Pseudomonas sepsis 13 months after HCT. A critical review of the literature and the treatment modalities for post-HCT PVAN are provided.
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- 2009
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46. The sesquiterpene lactone parthenolide induces apoptosis of human acute myelogenous leukemia stem and progenitor cells
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Derick R. Peterson, Dianna S. Howard, Craig T. Jordan, Monica L. Guzman, Xiaojie Li, Randall M. Rossi, and Lilliana Karnischky
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Transplantation, Heterologous ,Immunology ,Antineoplastic Agents ,Apoptosis ,Mice, SCID ,Biology ,Biochemistry ,Lactones ,Mice ,Myelogenous ,chemistry.chemical_compound ,Mice, Inbred NOD ,Cancer stem cell ,hemic and lymphatic diseases ,medicine ,Animals ,Humans ,Plenary Papers ,Parthenolide ,Progenitor cell ,Cells, Cultured ,Tumor Stem Cell Assay ,NF-kappa B ,Cell Biology ,Hematology ,medicine.disease ,Leukemia, Myeloid, Acute ,Haematopoiesis ,Leukemia ,chemistry ,Neoplastic Stem Cells ,Cancer research ,Tumor Suppressor Protein p53 ,Stem cell ,Blast Crisis ,Reactive Oxygen Species ,Sesquiterpenes ,Neoplasm Transplantation ,Chronic myelogenous leukemia - Abstract
Recent studies have described malignant stem cells as central to the initiation, growth, and potential relapse of acute and chronic myelogenous leukemia (AML and CML). Because of their important role in pathogenesis, rare and biologically distinct leukemia stem cells (LSCs) represent a critical target for therapeutic intervention. However, to date, very few agents have been shown to directly target the LSC population. The present studies demonstrate that parthenolide (PTL), a naturally occurring small molecule, induces robust apoptosis in primary human AML cells and blast crisis CML (bcCML) cells while sparing normal hematopoietic cells. Furthermore, analysis of progenitor cells using in vitro colony assays, as well as stem cells using the nonobese diabetic/severe combined immunodeficient (NOD/SCID) xenograft model, show that PTL also preferentially targets AML progenitor and stem cell populations. Notably, in comparison to the standard chemotherapy drug cytosine arabinoside (Ara-C), PTL is much more specific to leukemia cells. The molecular mechanism of PTL-mediated apoptosis is strongly associated with inhibition of nuclear factor κ B (NF-κB), proapoptotic activation of p53, and increased reactive oxygen species (ROS). On the basis of these findings, we propose that the activity of PTL triggers LSC-specific apoptosis and as such represents a potentially important new class of drugs for LSC-targeted therapy.
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- 2005
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47. Acute Graft-Versus-Host Disease in the Setting of T Cell Depletion: Validation of a New Agvhd Risk Score
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Stacey Slone, Hayder Saeed, Trey Becton, Gregory Monohan, Gerhard C. Hildebrandt, Roger H. Herzig, Dianna S. Howard, and Swati Yalamanchi
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Transplantation ,medicine.medical_specialty ,Framingham Risk Score ,business.industry ,Internal medicine ,Acute graft versus host disease ,medicine ,T-cell depletion ,Hematology ,business ,Gastroenterology - Published
- 2016
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48. Timing of Salvage Therapy and Autologous Hematopoietic Cell Transplant in Relapsed Hodgkin and Non Hodgkin Lymphoma
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Nora F. Fino, Gordon L. Phillips, David D. Hurd, Zanetta S. Lamar, Dianna S. Howard, Zachariah A. McIver, and Rakhee Vaidya
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Oncology ,medicine.medical_specialty ,Transplantation ,Hematopoietic cell ,business.industry ,Internal medicine ,Salvage therapy ,Hodgkin lymphoma ,Medicine ,Hematology ,business - Published
- 2016
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49. Relationship of CMV Reactivation and Rabbit Antithymocyte Globulin Administration in Allogeneic Stem Cell Transplant Patients
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LeAnne Kennedy, Marie Cavalier, and Dianna S. Howard
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Transplantation ,business.industry ,Hematology ,Cmv reactivation ,03 medical and health sciences ,Rabbit antithymocyte globulin ,0302 clinical medicine ,Immunology ,Medicine ,Transplant patient ,030212 general & internal medicine ,Stem cell ,business ,030215 immunology - Published
- 2017
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50. Nuclear factor-κB is constitutively activated in primitive human acute myelogenous leukemia cells
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Barry Grimes, Selina M. Luger, Dianna S. Howard, Sarah J. Neering, Monica L. Guzman, Donna Upchurch, Craig T. Jordan, and David A. Rizzieri
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Myeloid ,Leupeptins ,Immunology ,Population ,CD34 ,Antigens, CD34 ,Bone Marrow Cells ,Biology ,CD38 ,Biochemistry ,Culture Media, Serum-Free ,Antigens, CD ,Reference Values ,Cancer stem cell ,Tumor Cells, Cultured ,medicine ,Humans ,Enzyme Inhibitors ,Progenitor cell ,education ,Cells, Cultured ,education.field_of_study ,Reverse Transcriptase Polymerase Chain Reaction ,Stem Cells ,Cell Cycle ,NF-kappa B ,Cell Biology ,Hematology ,Flow Cytometry ,Hematopoietic Stem Cells ,medicine.disease ,Actins ,Leukemia, Myeloid, Acute ,Leukemia ,medicine.anatomical_structure ,Cancer research ,Stem cell - Abstract
Human acute myelogenous leukemia (AML) is thought to arise from a rare population of malignant stem cells. Cells of this nature, herein referred to as leukemic stem cells (LSCs), have been documented for nearly all AML subtypes and appear to fulfill the criteria for stem cells in that they are self-renewing and give rise to the cells found in many leukemic populations. Because these cells are likely to be critical for the genesis and perpetuation of leukemic disease, the present studies sought to characterize unique molecular properties of the LSC population, with particular emphasis on the transcription factor, nuclear factor-κB (NF-κB). Previous experiments have shown that unstimulated human CD34+ progenitor cells do not express NF-κB. In contrast, primary AML CD34+ cells display readily detectable NF-κB activity as assessed by electrophoretic mobility shift assay and gene expression studies. Furthermore, detailed analyses of enriched AML stem cells (CD34+/CD38−/CD123+) indicate that NF-κB is also active in the LSC population. Given the expression of NF-κB in leukemic, but not normal primitive cells, the hypothesis that inhibition of NF-κB might induce leukemia-specific apoptosis was tested by treating primary cells with the proteasome inhibitor MG-132, a well-known inhibitor of NF-κB. Leukemic CD34+/CD38− cells displayed a rapid induction of cell death in response to MG-132, whereas normal CD34+/CD38− cells showed little if any effect. Taken together, these data indicate that primitive AML cells aberrantly express NF-κB and that the presence of this factor may provide unique opportunities to preferentially ablate LSCs.
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- 2001
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