64 results on '"Stockerl-Goldstein KE"'
Search Results
2. The Dynamics of Financial Toxicity in Multiple Myeloma.
- Author
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Fiala MA, Silberstein AE, Schroeder MA, Stockerl-Goldstein KE, and Vij R
- Subjects
- Humans, Male, Aged, Financial Stress, Surveys and Questionnaires, Longitudinal Studies, Duration of Therapy, Multiple Myeloma
- Abstract
Introduction/background: People with multiple myeloma are at risk for financial toxicity due to the high cost of treatment and prolonged treatment duration. However, little data exist regarding financial toxicity among people with myeloma., Patients and Methods: In this study, a cohort of 135 patients were recruited from an ongoing observational trial to complete the Comprehensive Score for financial Toxicity (COST). Participants were sent follow-up surveys at 3, 6, and 12 months., Results: The median age was 68 years; the majority were non-Hispanic whites (88%), male (63%), held a college degree (61%), and had left the workforce (70%). The median time from myeloma diagnosis was 28 months. The median COST score was 27; 48% of participants had a score below 27 and considered to have financial toxicity. The only characteristic associated with financial toxicity was a college degree. After controlling for other covariates, those with a college education were 69% less likely to have financial toxicity. Of the 108 participants who completed a follow-up survey, 34% reported changes in their financial toxicity status at a subsequent time point. Transitioning from not having financial toxicity to having financial toxicity was more common than the reverse., Conclusion: Because financial toxicity is a dynamic process, which patients are experiencing it at any given time is difficult to predict. Focusing the research agenda on improved detection and intervention may be warranted., (Copyright © 2023 Elsevier Inc. All rights reserved.)
- Published
- 2023
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- View/download PDF
3. Patients Recently Treated for B-lymphoid Malignancies Show Increased Risk of Severe COVID-19.
- Author
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Rubinstein SM, Bhutani D, Lynch RC, Hsu CY, Shyr Y, Advani S, Mesa RA, Mishra S, Mundt DP, Shah DP, Sica RA, Stockerl-Goldstein KE, Stratton C, Weiss M, Beeghly-Fadiel A, Accordino M, Assouline SE, Awosika J, Bakouny Z, Bashir B, Berg S, Bilen MA, Castellano CA, Cogan JC, Kc D, Friese CR, Gupta S, Hausrath D, Hwang C, Johnson NA, Joshi M, Kasi A, Klein EJ, Koshkin VS, Kuderer NM, Kwon DH, Labaki C, Latif T, Lau E, Li X, Lyman GH, McKay RR, Nagaraj G, Nizam A, Nonato TK, Olszewski AJ, Polimera HV, Portuguese AJ, Puc MM, Razavi P, Rosovski R, Schmidt A, Shah SA, Shastri A, Su C, Torka P, Wise-Draper TM, Zubiri L, Warner JL, and Thompson MA
- Subjects
- COVID-19 Testing, Humans, Risk Factors, SARS-CoV-2, COVID-19 epidemiology, Lymphatic Diseases, Neoplasms epidemiology
- Abstract
Patients with B-lymphoid malignancies have been consistently identified as a population at high risk of severe COVID-19. Whether this is exclusively due to cancer-related deficits in humoral and cellular immunity, or whether risk of severe COVID-19 is increased by anticancer therapy, is uncertain. Using data derived from the COVID-19 and Cancer Consortium (CCC19), we show that patients treated for B-lymphoid malignancies have an increased risk of severe COVID-19 compared with control populations of patients with non-B-lymphoid malignancies. Among patients with B-lymphoid malignancies, those who received anticancer therapy within 12 months of COVID-19 diagnosis experienced increased COVID-19 severity compared with patients with non-recently treated B-lymphoid malignancies, after adjustment for cancer status and several other prognostic factors. Our findings suggest that patients recently treated for a B-lymphoid malignancy are at uniquely high risk for severe COVID-19., Significance: Our study suggests that recent therapy for a B-lymphoid malignancy is an independent risk factor for COVID-19 severity. These findings provide rationale to develop mitigation strategies targeted at the uniquely high-risk population of patients with recently treated B-lymphoid malignancies. This article is highlighted in the In This Issue feature, p. 171., (©2022 American Association for Cancer Research.)
- Published
- 2022
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4. Machine learning-based scoring models to predict hematopoietic stem cell mobilization in allogeneic donors.
- Author
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Xiang J, Shi M, Fiala MA, Gao F, Rettig MP, Uy GL, Schroeder MA, Weilbaecher KN, Stockerl-Goldstein KE, Mollah S, and DiPersio JF
- Subjects
- Antigens, CD34 metabolism, Granulocyte Colony-Stimulating Factor pharmacology, Granulocyte-Macrophage Colony-Stimulating Factor, Hematopoietic Stem Cell Mobilization, Humans, Machine Learning, Retrospective Studies, Hematopoietic Stem Cell Transplantation, Heterocyclic Compounds pharmacology
- Abstract
Mobilized peripheral blood has become the primary source of hematopoietic stem cells for both autologous and allogeneic stem cell transplantation. Granulocyte colony-stimulating factor (G-CSF) is currently the standard agent used in the allogeneic setting. Despite the high mobilization efficacy in most donors, G-CSF requires 4-5 days of daily administration, and a small percentage of the donors fail to mobilize an optimal number of stem cells necessary for a safe allogeneic stem cell transplant. In this study, we retrospectively reviewed 1361 related allogeneic donors who underwent stem cell mobilization at Washington University. We compared the standard mobilization agent G-CSF with five alternative mobilization regimens, including GM-CSF, G-CSF+GM-CSF, GM-CSF + Plerixafor, Plerixafor and BL-8040. Cytokine-based mobilization strategies (G-CSF or in combination with GM-CSF) induce higher CD34 cell yield after 4-5 consecutive days of treatment, while CXCR4 antagonists (plerixafor and BL-8040) induce significantly less but rapid mobilization on the same day. Next, using a large dataset containing the demographic and baseline laboratory data from G-CSF-mobilized donors, we established machine learning (ML)-based scoring models that can be used to predict patients who may have less than optimal stem cell yields after a single leukapheresis session. To our knowledge, this is the first prediction model at the early donor screening stage, which may help identify allogeneic stem cell donors who may benefit from alternative approaches to enhance stem cell yields, thus ensuring safe and effective stem cell transplantation., (© 2022 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)
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- 2022
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5. Systemic IL-15 promotes allogeneic cell rejection in patients treated with natural killer cell adoptive therapy.
- Author
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Berrien-Elliott MM, Becker-Hapak M, Cashen AF, Jacobs M, Wong P, Foster M, McClain E, Desai S, Pence P, Cooley S, Brunstein C, Gao F, Abboud CN, Uy GL, Westervelt P, Jacoby MA, Pusic I, Stockerl-Goldstein KE, Schroeder MA, DiPersio JF, Soon-Shiong P, Miller JS, and Fehniger TA
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- Allogeneic Cells immunology, Female, Humans, Interleukin-15 immunology, Killer Cells, Natural immunology, Male, Antineoplastic Agents administration & dosage, CD8-Positive T-Lymphocytes immunology, Hematopoietic Stem Cell Transplantation, Immunotherapy, Adoptive, Interleukin-15 administration & dosage, Killer Cells, Natural transplantation, Leukemia, Myeloid, Acute immunology, Leukemia, Myeloid, Acute therapy, Recombinant Fusion Proteins administration & dosage
- Abstract
Natural killer (NK) cells are a promising alternative to T cells for cancer immunotherapy. Adoptive therapies with allogeneic, cytokine-activated NK cells are being investigated in clinical trials. However, the optimal cytokine support after adoptive transfer to promote NK cell expansion, and persistence remains unclear. Correlative studies from 2 independent clinical trial cohorts treated with major histocompatibility complex-haploidentical NK cell therapy for relapsed/refractory acute myeloid leukemia revealed that cytokine support by systemic interleukin-15 (IL-15; N-803) resulted in reduced clinical activity, compared with IL-2. We hypothesized that the mechanism responsible was IL-15/N-803 promoting recipient CD8 T-cell activation that in turn accelerated donor NK cell rejection. This idea was supported by increased proliferating CD8+ T-cell numbers in patients treated with IL-15/N-803, compared with IL-2. Moreover, mixed lymphocyte reactions showed that IL-15/N-803 enhanced responder CD8 T-cell activation and proliferation, compared with IL-2 alone. Additionally, IL-15/N-803 accelerated the ability of responding T cells to kill stimulator-derived memory-like NK cells, demonstrating that additional IL-15 can hasten donor NK cell elimination. Thus, systemic IL-15 used to support allogeneic cell therapy may paradoxically limit their therapeutic window of opportunity and clinical activity. This study indicates that stimulating patient CD8 T-cell allo-rejection responses may critically limit allogeneic cellular therapy supported with IL-15. This trial was registered at www.clinicaltrials.gov as #NCT03050216 and #NCT01898793., (© 2022 by The American Society of Hematology.)
- Published
- 2022
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6. Autologous stem cell transplant for patients with multiple myeloma between ages 75 and 78.
- Author
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Fiala MA, King J, Feinberg D, Goldsmith SR, Schroeder MA, Ghobadi A, Stockerl-Goldstein KE, Vij R, and Wildes TM
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- Aged, Humans, Stem Cell Transplantation, Transplantation, Autologous, Hematopoietic Stem Cell Transplantation, Multiple Myeloma therapy
- Published
- 2021
- Full Text
- View/download PDF
7. Association of clinical factors and recent anticancer therapy with COVID-19 severity among patients with cancer: a report from the COVID-19 and Cancer Consortium.
- Author
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Grivas P, Khaki AR, Wise-Draper TM, French B, Hennessy C, Hsu CY, Shyr Y, Li X, Choueiri TK, Painter CA, Peters S, Rini BI, Thompson MA, Mishra S, Rivera DR, Acoba JD, Abidi MZ, Bakouny Z, Bashir B, Bekaii-Saab T, Berg S, Bernicker EH, Bilen MA, Bindal P, Bishnoi R, Bouganim N, Bowles DW, Cabal A, Caimi PF, Chism DD, Crowell J, Curran C, Desai A, Dixon B, Doroshow DB, Durbin EB, Elkrief A, Farmakiotis D, Fazio A, Fecher LA, Flora DB, Friese CR, Fu J, Gadgeel SM, Galsky MD, Gill DM, Glover MJ, Goyal S, Grover P, Gulati S, Gupta S, Halabi S, Halfdanarson TR, Halmos B, Hausrath DJ, Hawley JE, Hsu E, Huynh-Le M, Hwang C, Jani C, Jayaraj A, Johnson DB, Kasi A, Khan H, Koshkin VS, Kuderer NM, Kwon DH, Lammers PE, Li A, Loaiza-Bonilla A, Low CA, Lustberg MB, Lyman GH, McKay RR, McNair C, Menon H, Mesa RA, Mico V, Mundt D, Nagaraj G, Nakasone ES, Nakayama J, Nizam A, Nock NL, Park C, Patel JM, Patel KG, Peddi P, Pennell NA, Piper-Vallillo AJ, Puc M, Ravindranathan D, Reeves ME, Reuben DY, Rosenstein L, Rosovsky RP, Rubinstein SM, Salazar M, Schmidt AL, Schwartz GK, Shah MR, Shah SA, Shah C, Shaya JA, Singh SRK, Smits M, Stockerl-Goldstein KE, Stover DG, Streckfuss M, Subbiah S, Tachiki L, Tadesse E, Thakkar A, Tucker MD, Verma AK, Vinh DC, Weiss M, Wu JT, Wulff-Burchfield E, Xie Z, Yu PP, Zhang T, Zhou AY, Zhu H, Zubiri L, Shah DP, Warner JL, and Lopes G
- Subjects
- Aged, COVID-19 Testing, Female, Humans, Male, Pandemics, SARS-CoV-2, COVID-19, Neoplasms drug therapy, Neoplasms epidemiology
- Abstract
Background: Patients with cancer may be at high risk of adverse outcomes from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. We analyzed a cohort of patients with cancer and coronavirus 2019 (COVID-19) reported to the COVID-19 and Cancer Consortium (CCC19) to identify prognostic clinical factors, including laboratory measurements and anticancer therapies., Patients and Methods: Patients with active or historical cancer and a laboratory-confirmed SARS-CoV-2 diagnosis recorded between 17 March and 18 November 2020 were included. The primary outcome was COVID-19 severity measured on an ordinal scale (uncomplicated, hospitalized, admitted to intensive care unit, mechanically ventilated, died within 30 days). Multivariable regression models included demographics, cancer status, anticancer therapy and timing, COVID-19-directed therapies, and laboratory measurements (among hospitalized patients)., Results: A total of 4966 patients were included (median age 66 years, 51% female, 50% non-Hispanic white); 2872 (58%) were hospitalized and 695 (14%) died; 61% had cancer that was present, diagnosed, or treated within the year prior to COVID-19 diagnosis. Older age, male sex, obesity, cardiovascular and pulmonary comorbidities, renal disease, diabetes mellitus, non-Hispanic black race, Hispanic ethnicity, worse Eastern Cooperative Oncology Group performance status, recent cytotoxic chemotherapy, and hematologic malignancy were associated with higher COVID-19 severity. Among hospitalized patients, low or high absolute lymphocyte count; high absolute neutrophil count; low platelet count; abnormal creatinine; troponin; lactate dehydrogenase; and C-reactive protein were associated with higher COVID-19 severity. Patients diagnosed early in the COVID-19 pandemic (January-April 2020) had worse outcomes than those diagnosed later. Specific anticancer therapies (e.g. R-CHOP, platinum combined with etoposide, and DNA methyltransferase inhibitors) were associated with high 30-day all-cause mortality., Conclusions: Clinical factors (e.g. older age, hematological malignancy, recent chemotherapy) and laboratory measurements were associated with poor outcomes among patients with cancer and COVID-19. Although further studies are needed, caution may be required in utilizing particular anticancer therapies., Clinical Trial Identifier: NCT04354701., Competing Interests: Disclosure JDA reports research funding to the institution from Tesaro, outside the submitted work. ZB reports nonfinancial support from Bristol Myers Squibb and grants from Genentech/imCORE, outside the submitted work. BB reports research funding to the institution from Boehringer Ingelheim, Bicycle Therapeutics, Syros Pharmaceuticals, and Ikena Oncology, all outside the submitted work. TB-S reports research funding to the institution from Agios, Arys, Boston Biomedical, Bayer, Amgen, Merck, Celgene, Lilly, Ipsen, Clovis, Seattle Genetics, Array Biopharma, Genentech, Novartis, Mirati, Merus, AbGenomics, Incyte, Pfizer, BMS; consulting (to institution) for Ipsen, Array Biopharma, Pfizer, Seattle Genetics, Bayer, Genentech, Incyte, and Merck; consulting (to self) for AbbVie, Boehringer Ingelheim, Janssen, Eisai, Daiichi Sankyo, Natera, Treos Bio, Celularity, Exact Science, Sobi, BeiGene, Xilis, Astra Zeneca, and Foundation Medicine; serving on Independent Data Monitoring Committee/Data and Safety Monitoring Board (to self) for AstraZeneca, Exelixis, Lilly, PanCAN, and 1Globe; positions on Scientific Advisory Board for Imugene, Immuneering, and Sun Biopharma; and inventions/patents (WO/2018/183488 and WO/2019/055687), all outside the submitted work. SB reports being on advisory boards for Bristol Meyers Squibb and Seattle Genetics. MAB reports personal fees from Exelixis, Bristol-Myers Squibb, Bayer, Eisai, Pfizer, AstraZeneca, Janssen, Genomic Health, Nektar, and Sanofi; grants from Xencor, Bayer, Bristol-Myers Squibb, Genentech/Roche, Seattle Genetics, Incyte, Nektar, AstraZeneca, Tricon Pharmaceuticals, Peloton Therapeutics, and Pfizer, outside the submitted work. NB reports honoraria from Novartis, Pfizer, Roche, and Lilly, outside the submitted work. DWB reports research funding to the institution from Exelixis, Ayala, Merck, and Elevar, all outside the submitted work. DDC declares consulting or advisory role with Exelixis, outside the submitted work. TKC reports institutional and personal research support from Alexion, Analysis Group, AstraZeneca, Aveo, Bayer, Bristol Myers-Squibb/ER Squibb and sons LLC, Calithera, Cerulean, Corvus, Eisai, Exelixis, F. Hoffmann-La Roche, Foundation Medicine Inc., Genentech, GlaxoSmithKline, Ipsen, Lilly, Merck, Novartis, Peloton, Pfizer, Prometheus Labs, Roche, Roche Products Limited, Sanofi/Aventis, Takeda, Tracon; consulting/honoraria or advisory role with Alexion, Analysis Group, AstraZeneca, Aveo, Bayer, Bristol Myers-Squibb/ER Squibb and sons LLC, Cerulean, Corvus, Eisai, EMD Serono, Exelixis, Foundation Medicine Inc., Genentech, GlaxoSmithKline, Heron Therapeutics, Infinity Pharma, Ipsen, Jansen Oncology, IQVIA, Lilly, Merck, NCCN, Novartis, Peloton, Pfizer, Pionyr, Prometheus Labs, Roche, Sanofi/Aventis, Surface Oncology, Tempest, Up-to-Date; CME-related events (e.g. OncLive, PVI, MJH Life Sciences); stock ownership in Pionyr, Tempest; patents filed, royalties, or other intellectual properties related to biomarkers of immune checkpoint blockers; fees for travel, accommodations, expenses, medical writing in relation to consulting, advisory roles, or honoraria; and no speaker's bureau; also supported in part by the Dana-Farber/Harvard Cancer Center Kidney SPORE and Program, the Kohlberg Chair at Harvard Medical School and the Trust Family, Michael Brigham, and Loker Pinard Funds for Kidney Cancer Research at DFCI. DBD reports consulting for Ipsen, Boehringer Ingelheim; ASCO Young Investigator Award from Conquer Cancer Foundation, outside the submitted work. AE reports grant support from AstraZeneca, outside the submitted work. DF reports research funding to the institution from Viracor-Eurofins and Astellas, all outside the submitted work. LAF reports clinical trial funding to the institution from BMS, EMD Serono, Pfizer, Merck KGaA, Array, Kartos, Merck, and Incyte, ECOG-ACRIN study funding from Array; and personal fees from Elsevier and Via Oncology, outside the submitted work. DBF reports honoraria from Castle Biosciences. SMG reports Honoraria from AstraZeneca, Merck, Genentech/Roche; consulting or advisory role with Genentech/Roche, AstraZeneca, Bristol-Myers Squibb, Takeda, Xcovery, Boehringer Ingelheim, Novocure, Daiichi Sankyo, Novartis, Jazz Pharmaceuticals, Blueprint Medicines, Eli Lilly, Pfizer, Janssen Oncology; research funding (to self) from Merck, AstraZeneca; research funding (to institution) from Genentech/Roche, Merck, Blueprint Medicines, ARIAD/Takeda, Astellas Pharma, Lycera, Daiichi Sankyo, IMAB, Nektar, AstraZeneca, Pfizer, Amgen; travel, accommodations, expenses from Genentech/Roche, Merck; and other relationship from AstraZeneca, all outside the submitted work. MDG reports personal fees from Genentech, Pfizer, Astra Zeneca, Merck, Bristol Myers Squib, Dragonfly, Dracen, Seattle Genetics, and Astellas, outside the submitted work. PG reports consulting fees from AstraZeneca, Bayer, Bristol-Myers Squibb, Clovis Oncology, Dyania Health, Driver, EMD Serono, Exelixis, Foundation Medicine, Genentech/Roche, Genzyme, GlaxoSmithKline, Heron Therapeutics, Immunomedics, Infinity Pharmaceuticals, Janssen, Merck, Mirati Therapeutics, Pfizer, Seattle Genetics, QED Therapeutics; research funding to institution from Merck, Mirati Therapeutics, Pfizer, Clovis Oncology, Bavarian Nordic, Immunomedics, Debiopharm, Bristol-Myers Squibb, QED Therapeutics, GlaxoSmithKline, and Kure It Cancer Research, all outside the submitted work. SG reports research funding to the institution from AstraZeneca and consulting/advisory role with Puma Biotechnology. SG reports consultancy fees from BMS, Merck, AstraZeneca, Seattle Genetics, Pfizer; and speaker fees from Seattle Genetics and Janssen, all outside the submitted work. TRH reports consulting or advisory role with Curium, ScioScientific, TERUMO, Lexicon, Ipsen, Advanced Accelerator; research funding from Ipsen, ArQule, Agios, Thermo Fisher Scientific, Basilea. BH reports research funding to the institution from Amgen, AbbVie, BI, Mirati, Merck, Eli-Lilly, AstraZeneca, BMS, Novartis, GSK, Pfizer, Advaxis, and Guardant Health; consulting/advisory role with Merck, BMS, Genentech, AstraZeneca, Amgen, Novartis, TPT, VI, Guardant Health; and honoraria from PER and OncLive, all outside the submitted work. JEH reports research funding from Regeneron and Dendreon; and travel, accommodations, and expenses from Genzyme. CH reports funding from the Henry Ford Cancer Institute supporting the current work; research funding to institution from Merck, Exelixis, Bayer, AstraZeneca, Genentech, Dendreon and Bausch; personal fees from Sanofi/Genzyme, Dendreon, Exelixis, Bristol Myers Squibb, Astellas, Medivation, Bayer, and Janssen Scientific, all outside the submitted work; and stock ownership by an immediate family member in Johnson and Johnson. DBJ reports advisory board participation for Array Biopharma, BMS, Catalyst Biopharma, Iovance, Jansen, Merck, Novartis, and OncoSec, and receives research funding from BMS and Incyte, all outside the submitted work. AK reports support to his institution from TESARO, Halozyme, Geistlich Pharma, Astellas Pharma, and Rafael Pharmaceuticals; and honoraria from OncLive, outside the submitted work. ARK (or an immediate family member) has currently or during the past 2 years owned stock or held an ownership interest in Merck, Sanofi, and BMS. VSK reports personal fees from Pfizer, Janssen, Dendreon, AstraZeneca, Seattle Genetics, and Clovis; grants (for institution) from Nektar, Novartis/Endocyte, Janssen, Clovis, and Prostate Cancer Foundation, all outside the submitted work. NMK reports personal fees from G1 Therapeutics, Invitae, Beyond Spring, Spectrum, BMS, Janssen, and Total Health, all outside the submitted work. PEL reports consulting/advisory role with Pfizer, Merck, Teva, BI, and Astra Zeneca, all outside the submitted work. AL-B reports personal fees from PSI CRO, Bayer, Blueprint, Astra-Zeneca, Medidata, Taiho, QED, Cardinal Health, BrightInsight, The Lynx Group, Boston Biomedical, Amgen, Bayer, Guardant, Natera, Eisai, Ipsen, and Merck; and stock options from Massive Bio, outside the submitted work. GdLL reports honoraria from Boehringer Ingelheim; consulting or advisory role for Pfizer and AstraZeneca; research funding from AstraZeneca; funding to his institution from Merck Sharp & Dohme, EMD Serono, AstraZeneca, Blueprint Medicines, Tesaro, Bavarian Nordic, NOVARTIS, G1 Therapeutics, Adaptimmune, BMS, GSK, AbbVie, Rgenix, Pfizer, Roche, Genentech, Lilly, and Janssen; travel, accommodations, and expenses from Boehringer Ingelheim, Pfizer, E.R. Squibb Sons, LLC, Janssen. GHL reports grants from AMGEN (institution); personal fees from G1 Therapeutics, TEVA, Samsung Bioepis, Beyond Spring, and Merck, outside the submitted work. RRM reports research funding from Bayer, Pfizer, Tempus; serves on Advisory Board for AstraZeneca, Bayer, Bristol Myers Squibb, Calithera, Exelixis, Janssen, Merck, Novartis, Pfizer, Sanofi, Tempus; is a consultant for Dendreon, Vividion; and serves on the molecular tumor board at Caris. RAM grants from Incyte, CTI, AbbVie, and Celgene; personal fees from Novartis, Genentech, Sierra Oncology, La Jolla, and Samus, outside the submitted work. VM has currently or during the past 2 years employment and stock or other ownership interest with Johnson & Johnson, all outside the submitted work. GN reports research funding to the institution from Novartis, all outside the submitted work. JN reports personal fees from AstraZeneca, Clovis Oncology; all outside the submitted work. CAP (or an immediate family member) has currently or during the past 2 years owned stock or held an ownership interest in Pfizer, Epizyme, Inovio, OPKO Health Inc, Roche. JMP reports grant from Dana-Farber/Harvard Cancer Center Breast SPORE Program, outside the submitted work. PP reports receiving payment for speakers' bureau from Novartis, Daichi Sankyo, Genentech, Seattle Genetics, and Pfizer, all outside the submitted work. NAP reports personal fees from Eli Lilly, Merck, BMS, Genentech, AstraZeneca, Inivata, and Regeneron, outside the submitted work. SP reports personal fees from AbbVie, Amgen, AstraZeneca, Bayer, Biocartis, Boehringer-Ingelheim, Bristol-Myers Squibb, Clovis, Daiichi Sankyo, Debiopharm, Eli Lilly, F. Hoffmann-La Roche, Foundation Medicine, Illumina, Janssen, Merck Sharp and Dohme, Merck Serono, Merrimack, Novartis, Pharma Mar, Pfizer, Regeneron, Sanofi, Seattle Genetics and Takeda, AstraZeneca, Boehringer-Ingelheim, Bristol-Myers Squibb, Eli Lilly, F. Hoffmann-La Roche, Merck Sharp and Dohme, Novartis, Pfizer, and Takeda; nonfinancial support from Amgen, AstraZeneca, Boehringer-Ingelheim, Bristol-Meyers Squibb, Clovis, F. Hoffmann-La Roche, Illumina, Merck Sharp and Dohme, Merck Serono, Novartis, Pfizer, and Sanofi; and personal fees from BioInvent (all fees to institution), outside the submitted work. DYR reports consulting/advisory role with and coverage of travel/accommodation expenses by Castle Biosciences, all outside the submitted work. BIR reports grants, personal fees, and nonfinancial support from Merck; grants and personal fees from BMS, Pfizer, Aveo, and Genentech; grants from Astra Zeneca; personal fees from Synthorx, 3D Medicines, Aravive, Surface Oncology, and Arrowhead Therapeutics; and other from PTC Therapeutics, outside the submitted work. RPR reports research grants to her institution from BMS and Janssen and has worked as a consultant/advisor and received honoraria from BMS and Janssen, all of which are outside the scope of submitted work. ALS reports travel support provided by Pfizer and Astellas. GKS reports personal fees from Apexigen, Array, Epizyme, GenCirq, Daiichi Sankyo, Fortress, Iovance Biotherapeutics, Bayer Pharmaceuticals, Pfizer Oncology, Array Advisory Board, Oncogenuity, Puretech, PTC Therapeutics, Ellipses Pharma, Concarlo; advisory board for Bionaut; grants from Astex; stock ownership in Pfizer, all outside the submitted work. SS reports stock and other ownership interests in Grand Rounds, Janssen, and Natera. YS reports honoraria from Boehringer Ingelheim, AstraZeneca, Novartis, and Eisai; consulting or advisory role with Pfizer, AstraZeneca, Novartis, Roche, Genentech, and Janssen, all outside the submitted work. MAT reports travel support from Syapse, Royalties from UpToDate, Connect MDS/AML Registry in Celgene (now owned by BMS), Myeloma Registry in Takeda; stock ownership in Doximity; personal fees from VIA Oncology (now owned by Elsevier ClinicalPath), Adaptive Advisory Board, and GSK; he is the local PI for Clinical Trials in AbbVie, BMS, CRAB CTC, Denovo, Research Network, Eli Lilly, LynxBio, Strata Oncology, and TG Therapeutics, all outside the submitted work. AKV reports research funding to the institution from BMS, MedPacto, Prelude, iOnctura, and Janssen; honoraria from Acceleron and Novartis; consulting/advisory role with Stelexis and Janssen; stock or other ownership in Stelexis; and an immediate family member with employment/leadership with CereXis, all outside the submitted work. DCV reports honoraria and speakers' bureau fees from CSL Behring, Merck Canada, Novartis Canada, Takeda, and UCB Biosciences GmbH, and travel accommodations from CSL Behring, and Avir Pharma, all outside the submitted work. He is supported by the Fonds de la recherche en santé du Québec (FRQS) Clinician-Scientist Junior 2 program. JLW reports grants from the National Cancer Institute during the conduct of the study; personal fees from Westat and IBM Watson Health; and other from HemOnc.org LLC, outside the submitted work. TMW-D reports stock and other ownership interests in High Enroll; honoraria from Physicians' Education Resource; consulting or advisory roles with Shattuck Labs, Rakuten Medical, Exicure; research funding from Merck, AstraZeneca/MedImmune, Bristol-Myers Squibb, GlaxoSmithKline, Caris Life Sciences, GlaxoSmithKline; travel, accommodations, expenses from Merck, Bristol-Myers Squibb, Bexion, AstraZeneca/MedImmune, Caris Life Sciences, Lilly, and Tesaro, all outside the submitted work. EW-B reports work in a consultant/advisor role for Astellas and BMS; funding support from Pfizer Global Medical Grants; other for Exelixis; and an immediate family member with stock ownership in Immunomedics and Nektar, all outside the submitted work. TZ reports research funding (to Duke) from Pfizer, Janssen, Acerta, AbbVie, Novartis, Merrimack, OmniSeq, PGDx, Merck, Mirati, Astellas, and Regeneron; consulting/speaking role with Genentech Roche, Exelixis, Genomic Health, and Sanofi Aventis; and serves on the consulting/advisory board for AstraZeneca, Bayer, Pfizer, Foundation Medicine, Janssen, Amgen, BMS, Calithera, Dendreon, and MJH Associates; stock ownership/employment (spouse) from Capio Biosciences, Archimmune Therapeutics, and Nanorobotics. AYZ has currently or during the past 2 years owned stock or held an ownership interest in Gilead Sciences. LZ reports personal fees from MERCK, outside the submitted work. All others have declared no conflicts of interest., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)
- Published
- 2021
- Full Text
- View/download PDF
8. A multi-modal diagnostic model improves detection of cardiac amyloidosis among patients with diagnostic confirmation by cardiac biopsy.
- Author
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Zhang KW, Zhang R, Deych E, Stockerl-Goldstein KE, Gorcsan J 3rd, and Lenihan DJ
- Subjects
- Age Factors, Aged, Amyloid Neuropathies, Familial blood, Amyloid Neuropathies, Familial pathology, Amyloid Neuropathies, Familial physiopathology, Amyloidosis blood, Amyloidosis diagnosis, Amyloidosis pathology, Amyloidosis physiopathology, Biopsy, Blood Flow Velocity, Cardiomyopathies blood, Cardiomyopathies pathology, Clinical Decision Rules, Echocardiography, Electrocardiography, Female, Heart Ventricles diagnostic imaging, Heart Ventricles pathology, Humans, Immunoglobulin Light-chain Amyloidosis blood, Immunoglobulin Light-chain Amyloidosis pathology, Immunoglobulin Light-chain Amyloidosis physiopathology, Logistic Models, Male, Middle Aged, Multivariate Analysis, Natriuretic Peptide, Brain blood, Organ Size, Sex Factors, Troponin I blood, Amyloid Neuropathies, Familial diagnosis, Cardiomyopathies diagnosis, Immunoglobulin Light-chain Amyloidosis diagnosis
- Abstract
Background: Timely recognition of cardiac amyloidosis is clinically important, but the diagnosis is frequently delayed., Objectives: We sought to identify a multi-modality approach with the highest diagnostic accuracy in patients evaluated by cardiac biopsy, the diagnostic gold standard., Methods: Consecutive patients (N = 242) who underwent cardiac biopsy for suspected amyloidosis within an 18-year period were retrospectively identified. Cardiac biomarker, ECG, and echocardiography results were examined for correlation with biopsy-proven disease. A prediction model for cardiac amyloidosis was derived using multivariable logistic regression., Results: The overall cohort was characterized by elevated BNP (median 727 ng/mL), increased left ventricular wall thickness (IWT; median 1.7 cm), and reduced voltage-to-mass ratio (median 0.06 mm/[g/m
2 ]). One hundred and thirteen patients (46%) had either light chain (n = 53) or transthyretin (n = 60) amyloidosis by cardiac biopsy. A prediction model including age, relative wall thickness, left atrial pressure by E/e', and low limb lead voltage (<0.5 mV) showed good discrimination for cardiac amyloidosis with an optimism-corrected c-index of 0.87 (95% CI 0.83-0.92). The diagnostic accuracy of this model (79% sensitivity, 84% specificity) surpassed that of traditional screening parameters, such as IWT in the absence of left ventricular hypertrophy on ECG (98% sensitivity, 20% specificity) and IWT with low limb lead voltage (49% sensitivity, 91% specificity)., Conclusion: Among patients with an advanced infiltrative cardiomyopathy phenotype, traditional biomarker, ECG, and echocardiography-based screening tests have limited individual diagnostic utility for cardiac amyloidosis. A prediction algorithm including age, relative wall thickness, E/e', and low limb lead voltage improves the detection of cardiac biopsy-proven disease., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Dr. Zhang has received consulting fees from Eidos Therapeutics. Dr. Stockerl-Goldstein has received consulting fees from Celgene and grants from Millenium Pharmaceuticals, Janssen Pharmaceuticals, BioLineRx, Pfizer, and GlaxoSmithKline. Dr. Gorcsan has received research funding from GE Healthcare, TomTec, Hitachi, and Canon. Dr. Lenihan has received consulting fees from Lilly, Roche, Pfizer, Prothena, and Acorda, and research funding from Myocardial Solutions. All other authors have no corporate relationships to disclose., (Copyright © 2020 Elsevier Inc. All rights reserved.)- Published
- 2021
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9. Impact of a 40-Gene Targeted Panel Test on Physician Decision Making for Patients With Acute Myeloid Leukemia.
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Barnell EK, Newcomer KF, Skidmore ZL, Krysiak K, Anderson SR, Wartman LD, Oh ST, Welch JS, Stockerl-Goldstein KE, Vij R, Cashen AF, Pusic I, Westervelt P, Abboud CN, Ghobadi A, Uy GL, Schroeder MA, Dipersio JF, Politi MC, Spencer DH, Duncavage EJ, Ley TJ, Griffith M, Jacoby MA, and Griffith OL
- Subjects
- Adult, Aged, Aged, 80 and over, Female, Humans, Male, Middle Aged, Young Adult, Clinical Decision-Making, Genetic Testing methods, Leukemia, Myeloid, Acute genetics
- Abstract
Purpose: Physicians treating hematologic malignancies increasingly order targeted sequencing panels to interrogate recurrently mutated genes. The precise impact of these panels on clinical decision making is not well understood., Methods: Here, we report our institutional experience with a targeted 40-gene panel (MyeloSeq) that is used to generate a report for both genetic variants and variant allele frequencies for the treating physician (the limit of mutation detection is approximately one AML cell in 50)., Results: In total, 346 sequencing reports were generated for 325 patients with suspected hematologic malignancies over an 8-month period (August 2018 to April 2019). To determine the influence of genomic data on clinical care for patients with acute myeloid leukemia (AML), we analyzed 122 consecutive reports from 109 patients diagnosed with AML and surveyed the treating physicians with a standardized questionnaire. The panel was ordered most commonly at diagnosis (61.5%), but was also used to assess response to therapy (22.9%) and to detect suspected relapse (15.6%). The panel was ordered at multiple timepoints during the disease course for 11% of patients. Physicians self-reported that 50 of 114 sequencing reports (44%) influenced clinical care decisions in 44 individual patients. Influences were often nuanced and extended beyond identifying actionable genetic variants with US Food and Drug Administration-approved drugs., Conclusion: This study provides insights into how physicians are currently using multigene panels capable of detecting relatively rare AML cells. The most influential way to integrate these tools into clinical practice will be to perform prospective clinical trials that assess patient outcomes in response to genomically driven interventions., Competing Interests: The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated unless otherwise noted. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/po/author-center. Open Payments is a public database containing information reported by companies about payments made to US-licensed physicians (Open Payments). Erica K. BarnellEmployment: Geneoscopy Stock and Other Ownership Interests: Geneoscopy Patents, Royalties, Other Intellectual Property: Inventor of intellectual property in start-up company (Geneoscopy) Travel, Accommodations, Expenses: GeneoscopyKenneth F. NewcomerEmployment: Geneoscopy (I) Stock and Other Ownership Interests: Geneoscopy (I) Patents, Royalties, Other Intellectual Property: Inventor of intellectual property owned by Geneoscopy (I)Zachary L. SkidmoreStock and Other Ownership Interests: Aim Immunotech, Catalyst PharmaceuticalsKilannin KrysiakConsulting or Advisory Role: Gerson Lehrman GroupLukas D. WartmanConsulting or Advisory Role: Novartis, IncyteStephen T. OhConsulting or Advisory Role: Incyte, Novartis, Blueprint Medicines, Celgene, Kartos, CTI BioPharma Corp, PharmaEssentia, Disc Medicine, Constellation Pharmaceuticals Research Funding: Incyte (Inst), Gilead Sciences (Inst), CTI BioPharma Corp (Inst), Kartos (Inst), Celgene (Inst), Sierra Oncology (Inst), Blueprint Medicines (Inst), Constellation Pharmaceuticals (Inst)John S. WelchConsulting or Advisory Role: Archer Biosciences, Agios Research Funding: Janssen Oncology (Inst), Notable Labs (Inst)Keith E. Stockerl-GoldsteinStock and Other Ownership Interests: Abbott Laboratories, AbbVie Consulting or Advisory Role: Celgene Research Funding: GlaxoSmithKline, Takeda, BiolineRx, Janssen Other Relationship: CellerantRavi VijConsulting or Advisory Role: Bristol Myers Squibb, Celgene, Janssen, Sanofi, Karyopharm Therapeutics, Takeda, Genentech, AbbVie, Oncopeptides Research Funding: Takeda, Celgene, Bristol Myers Squibb Travel, Accommodations, Expenses: Celgene, Bristol Myers Squibb, Sanofi, Janssen, DAVAOncology, Karyopharm Therapeutics, Amgen, Takeda, AbbVieAmanda F. CashenConsulting or Advisory Role: Agios Speakers' Bureau: Novartis, CelgeneIskra PusicConsulting or Advisory Role: Kadmon, Incyte, SyndaxCamille N. AbboudStock and Other Ownership Interests: AbbVie (I), Abbott Laboratories (I), Gilead Sciences (I), Bristol Myers Squibb (I), Johnson & Johnson (I) Honoraria: Cardinal Health, Dova Pharmaceuticals, NkartaTherapeutics, Archer Biosciences Research Funding: Actinium Pharmaceuticals, Selvita (Inst), AlloVir (Inst), Forty-Seven (Inst)Armin GhobadiHonoraria: Kite Pharma Consulting or Advisory Role: Kite Pharma, Celgene, Amgen, Wugen Speakers' Bureau: Kite Pharma, AmgenGeoffrey L. UyConsulting or Advisory Role: Astellas Pharma, Genentech, Jazz PharmaceuticalsMark A. SchroederConsulting or Advisory Role: Astellas Pharma, Dova Pharmaceuticals, Flatiron Health, GlaxoSmithKline, Incyte, Partners Therapeutics, Partners Therapeutics, Pfizer Speakers' Bureau: AbbVie, Merck, TakedaJohn F. DiPersioStock and Other Ownership Interests: Magenta Therapeutics, Wugen Honoraria: Incyte Consulting or Advisory Role: Cellworks, Rivervest, Magenta Therapeutics, Incyte Research Funding: Amphivena Therapeutics (Inst), Macrogenics (Inst), Incyte (Inst), Wugen (Inst), BiolineRx (Inst), Maxcyte (Inst), Bigelow Aerospace (Inst) Patents, Royalties, Other Intellectual Property: Patents: CD7 and CD2 knockout for CART to CD7 and CDL; Duvelisib for treatment of cytokine release syndrome; NT-17 to enhance CART survival; Novel WU mobilizing compounds (Inst); Selection of IMPDH mutant stem cells; IFNγ, upregulate MHCII for relapsed AML; Dextran-based molecules to detect CAR-T cells; Combining integrin inhibitor with chemokine binders, 016131; JAK and calcineurin inhibition, solid organ transplant; VLA4, gro-b; Triple combination–CXCR2, VLA-4, gro-b; Targeting IFNR/CSCR3 in GvHD; WU/SLU compounds VLA4 and CXCR2 (Inst) Travel, Accommodations, Expenses: Incyte, Macrogenics, Magenta TherapeuticsMary C. PolitiResearch Funding: MerckDavid H. SpencerConsulting or Advisory Role: Wugen Research Funding: IlluminaEric J. DuncavageStock and Other Ownership Interests: P&V Licensing Consulting or Advisory Role: Cofactor Genomics, Bristol Myers Squibb, Eli Lilly Open Payments Link: https://openpaymentsdata.cms.gov/physician/317379Timothy J. LeyResearch Funding: Rigel Patents, Royalties, Other Intellectual Property: Licenses for monoclonal antibodies and recombinant granzymesMeagan A. JacobyHonoraria: Takeda Research Funding: Geron (Inst), AbbVie (Inst), Jazz Pharmaceuticals (Inst), Aprea AB (Inst), Amphivena (Inst), Janssen (Inst) No other potential conflicts of interest were reported., (© 2021 by American Society of Clinical Oncology.)
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- 2021
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10. Multidimensional Analyses of Donor Memory-Like NK Cells Reveal New Associations with Response after Adoptive Immunotherapy for Leukemia.
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Berrien-Elliott MM, Cashen AF, Cubitt CC, Neal CC, Wong P, Wagner JA, Foster M, Schappe T, Desai S, McClain E, Becker-Hapak M, Foltz JA, Cooper ML, Jaeger N, Srivatsan SN, Gao F, Romee R, Abboud CN, Uy GL, Westervelt P, Jacoby MA, Pusic I, Stockerl-Goldstein KE, Schroeder MA, DiPersio J, and Fehniger TA
- Subjects
- Humans, Leukemia, Myeloid, Acute pathology, Immunotherapy, Adoptive methods, Killer Cells, Natural metabolism, Leukemia, Myeloid, Acute genetics
- Abstract
Natural killer (NK) cells are an emerging cancer cellular therapy and potent mediators of antitumor immunity. Cytokine-induced memory-like (ML) NK cellular therapy is safe and induces remissions in patients with acute myeloid leukemia (AML). However, the dynamic changes in phenotype that occur after NK-cell transfer that affect patient outcomes remain unclear. Here, we report comprehensive multidimensional correlates from ML NK cell-treated patients with AML using mass cytometry. These data identify a unique in vivo differentiated ML NK-cell phenotype distinct from conventional NK cells. Moreover, the inhibitory receptor NKG2A is a dominant, transcriptionally induced checkpoint important for ML, but not conventional NK-cell responses to cancer. The frequency of CD8α
+ donor NK cells is negatively associated with AML patient outcomes after ML NK therapy. Thus, elucidating the multidimensional dynamics of donor ML NK cells in vivo revealed critical factors important for clinical response, and new avenues to enhance NK-cell therapeutics. SIGNIFICANCE: Mass cytometry reveals an in vivo memory-like NK-cell phenotype, where NKG2A is a dominant checkpoint, and CD8α is associated with treatment failure after ML NK-cell therapy. These findings identify multiple avenues for optimizing ML NK-cell immunotherapy for cancer and define mechanisms important for ML NK-cell function. This article is highlighted in the In This Issue feature, p. 1775 ., (©2020 American Association for Cancer Research.)- Published
- 2020
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11. Clinical impact of COVID-19 on patients with cancer (CCC19): a cohort study.
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Kuderer NM, Choueiri TK, Shah DP, Shyr Y, Rubinstein SM, Rivera DR, Shete S, Hsu CY, Desai A, de Lima Lopes G Jr, Grivas P, Painter CA, Peters S, Thompson MA, Bakouny Z, Batist G, Bekaii-Saab T, Bilen MA, Bouganim N, Larroya MB, Castellano D, Del Prete SA, Doroshow DB, Egan PC, Elkrief A, Farmakiotis D, Flora D, Galsky MD, Glover MJ, Griffiths EA, Gulati AP, Gupta S, Hafez N, Halfdanarson TR, Hawley JE, Hsu E, Kasi A, Khaki AR, Lemmon CA, Lewis C, Logan B, Masters T, McKay RR, Mesa RA, Morgans AK, Mulcahy MF, Panagiotou OA, Peddi P, Pennell NA, Reynolds K, Rosen LR, Rosovsky R, Salazar M, Schmidt A, Shah SA, Shaya JA, Steinharter J, Stockerl-Goldstein KE, Subbiah S, Vinh DC, Wehbe FH, Weissmann LB, Wu JT, Wulff-Burchfield E, Xie Z, Yeh A, Yu PP, Zhou AY, Zubiri L, Mishra S, Lyman GH, Rini BI, and Warner JL
- Subjects
- Aged, Antiviral Agents therapeutic use, Azithromycin therapeutic use, Betacoronavirus, COVID-19, Cause of Death, Comorbidity, Coronavirus Infections drug therapy, Coronavirus Infections mortality, Databases, Factual, Female, Humans, Hydroxychloroquine therapeutic use, Male, Middle Aged, Neoplasms mortality, Neoplasms therapy, Pandemics, Pneumonia, Viral drug therapy, Pneumonia, Viral mortality, Prognosis, Risk Factors, SARS-CoV-2, COVID-19 Drug Treatment, Coronavirus Infections epidemiology, Neoplasms epidemiology, Pneumonia, Viral epidemiology
- Abstract
Background: Data on patients with COVID-19 who have cancer are lacking. Here we characterise the outcomes of a cohort of patients with cancer and COVID-19 and identify potential prognostic factors for mortality and severe illness., Methods: In this cohort study, we collected de-identified data on patients with active or previous malignancy, aged 18 years and older, with confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection from the USA, Canada, and Spain from the COVID-19 and Cancer Consortium (CCC19) database for whom baseline data were added between March 17 and April 16, 2020. We collected data on baseline clinical conditions, medications, cancer diagnosis and treatment, and COVID-19 disease course. The primary endpoint was all-cause mortality within 30 days of diagnosis of COVID-19. We assessed the association between the outcome and potential prognostic variables using logistic regression analyses, partially adjusted for age, sex, smoking status, and obesity. This study is registered with ClinicalTrials.gov, NCT04354701, and is ongoing., Findings: Of 1035 records entered into the CCC19 database during the study period, 928 patients met inclusion criteria for our analysis. Median age was 66 years (IQR 57-76), 279 (30%) were aged 75 years or older, and 468 (50%) patients were male. The most prevalent malignancies were breast (191 [21%]) and prostate (152 [16%]). 366 (39%) patients were on active anticancer treatment, and 396 (43%) had active (measurable) cancer. At analysis (May 7, 2020), 121 (13%) patients had died. In logistic regression analysis, independent factors associated with increased 30-day mortality, after partial adjustment, were: increased age (per 10 years; partially adjusted odds ratio 1·84, 95% CI 1·53-2·21), male sex (1·63, 1·07-2·48), smoking status (former smoker vs never smoked: 1·60, 1·03-2·47), number of comorbidities (two vs none: 4·50, 1·33-15·28), Eastern Cooperative Oncology Group performance status of 2 or higher (status of 2 vs 0 or 1: 3·89, 2·11-7·18), active cancer (progressing vs remission: 5·20, 2·77-9·77), and receipt of azithromycin plus hydroxychloroquine (vs treatment with neither: 2·93, 1·79-4·79; confounding by indication cannot be excluded). Compared with residence in the US-Northeast, residence in Canada (0·24, 0·07-0·84) or the US-Midwest (0·50, 0·28-0·90) were associated with decreased 30-day all-cause mortality. Race and ethnicity, obesity status, cancer type, type of anticancer therapy, and recent surgery were not associated with mortality., Interpretation: Among patients with cancer and COVID-19, 30-day all-cause mortality was high and associated with general risk factors and risk factors unique to patients with cancer. Longer follow-up is needed to better understand the effect of COVID-19 on outcomes in patients with cancer, including the ability to continue specific cancer treatments., Funding: American Cancer Society, National Institutes of Health, and Hope Foundation for Cancer Research., (Copyright © 2020 Elsevier Ltd. All rights reserved.)
- Published
- 2020
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12. Maintenance therapy following salvage autologous stem cell transplant in patients with multiple myeloma.
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Fiala MA, Vosuri V, Goldsmith S, Schroeder MA, Ghobadi A, Wildes TM, Stockerl-Goldstein KE, and Vij R
- Subjects
- Antineoplastic Combined Chemotherapy Protocols, Humans, Neoplasm Recurrence, Local, Salvage Therapy, Stem Cell Transplantation, Transplantation, Autologous, Treatment Outcome, Hematopoietic Stem Cell Transplantation, Multiple Myeloma drug therapy
- Published
- 2020
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13. A Phase I/II Trial of Carfilzomib, Pegylated Liposomal Doxorubicin, and Dexamethasone for the Treatment of Relapsed/Refractory Multiple Myeloma.
- Author
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Schroeder MA, Fiala MA, Huselton E, Cardone MH, Jaeger S, Jean SR, Shea K, Ghobadi A, Wildes T, Stockerl-Goldstein KE, and Vij R
- Subjects
- Aged, Antineoplastic Combined Chemotherapy Protocols adverse effects, Dexamethasone administration & dosage, Dexamethasone pharmacokinetics, Doxorubicin administration & dosage, Doxorubicin analogs & derivatives, Doxorubicin pharmacokinetics, Drug Monitoring, Drug Resistance, Neoplasm, Female, Humans, Male, Middle Aged, Multiple Myeloma mortality, Neoplasm Staging, Oligopeptides administration & dosage, Oligopeptides pharmacokinetics, Polyethylene Glycols administration & dosage, Polyethylene Glycols pharmacokinetics, Prognosis, Recurrence, Retreatment, Treatment Outcome, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Multiple Myeloma drug therapy, Multiple Myeloma pathology
- Abstract
Purpose: Pegylated liposomal doxorubicin (PLD) combined with bortezomib is an effective salvage regimen for relapsed refractory multiple myeloma (RRMM). Carfilzomib, a second-generation proteasome inhibitor, has clinical efficacy even among bortezomib-refractory patients., Patients and Methods: We performed a phase I/II trial of carfilzomib, PLD, and dexamethasone (KDD) with the primary endpoints being safety and efficacy (NCT01246063). Twenty-three patients were enrolled in the phase I portion and the MTD of carfilzomib was determined to be 56 mg/m
2 (days 1, 2, 8, 9, 15, and 16) when combined with PLD (30 mg/m2 on day 8) and dexamethasone (20 mg on days 1, 2, 8, 9, 15, and 16). Seventeen additional patients were enrolled in the phase II portion., Results: KDD was determined to be well tolerated with the only common grade 3/4 nonhematologic adverse events of infection. Grade 3/4 hematologic toxicity included lymphopenia (63%), thrombocytopenia (40%), anemia (40%), and neutropenia (28%). In the cohort of patients treated at the MTD, where median prior therapies were 2% and 42% were refractory to bortezomib, the overall response rate was 83% (20/24) with 54% (13/24) having a very good partial response or better. The median progression-free survival was 13.7 months (95% CI, 5.0-21.7)., Conclusions: This trial is the first to report outcomes using a triplet regimen of high-dose carfilzomib. KDD was well tolerated and appears efficacious in RRMM. Additional study is needed to more precisely determine patient outcomes with this regimen and its utility compared with other carfilzomib containing salvage regimens., (©2019 American Association for Cancer Research.)- Published
- 2019
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14. Emerging Therapeutics for the Treatment of Light Chain and Transthyretin Amyloidosis.
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Zhang KW, Stockerl-Goldstein KE, and Lenihan DJ
- Abstract
Cardiac amyloidosis is a restrictive cardiomyopathy that results from the deposition of misfolded light chain or transthyretin proteins, most commonly, in cardiac tissue. Traditionally, treatment options for light chain (AL) and transthyretin (ATTR) amyloidosis have been limited. However, there are now multiple novel therapeutics in development and several therapeutics recently approved that promise to revolutionize clinical management of AL and ATTR. Most of these agents disrupt specific stages of amyloidogenesis such as light chain or transthyretin protein production, formation of amyloidogenic intermediates, or amyloid fibril aggregation. Others aim to remove existing amyloid tissue deposits using monoclonal antibody technology. Although these advances represent an important step forward in the care of cardiac amyloidosis patients, additional studies are needed to define the optimal treatment paradigms for AL and ATTR and to validate clinical, imaging, or serum biomarker strategies that may confirm a cardiac response to therapy.
- Published
- 2019
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15. Results of an early access treatment protocol of daratumumab in United States patients with relapsed or refractory multiple myeloma.
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Chari A, Lonial S, Mark TM, Krishnan AY, Stockerl-Goldstein KE, Usmani SZ, Londhe A, Etheredge D, Fleming S, Liu B, Ukropec J, Lin TS, Jagannath S, and Nooka AK
- Subjects
- Acetates administration & dosage, Adult, Aged, Aged, 80 and over, Antibodies, Monoclonal adverse effects, Antineoplastic Agents, Immunological adverse effects, Cyclopropanes, Drug Administration Schedule, Drug Approval, Female, Humans, Infusions, Intravenous, Injection Site Reaction prevention & control, Male, Middle Aged, Quinolines administration & dosage, Sulfides, Survival Analysis, Treatment Outcome, United States, Antibodies, Monoclonal administration & dosage, Antineoplastic Agents, Immunological administration & dosage, Multiple Myeloma drug therapy, Neoplasm Recurrence, Local drug therapy
- Abstract
Background: Daratumumab is a human CD38-directed monoclonal antibody indicated for the treatment of relapsed and refractory multiple myeloma (MM)., Methods: A multicenter, open-label treatment protocol provided early access to daratumumab for patients who had progressive MM after they received ≥3 prior lines of therapy that included a proteasome inhibitor and an immunomodulatory agent or if they were refractory to both a proteasome inhibitor and an immunomodulatory agent. Patients received daratumumab 16 mg/kg weekly for 8 weeks, every other week for 16 weeks, and monthly until they developed disease progression, unacceptable toxicity, or 60 days after the drug gained US approval. Treatment-emergent grade ≥3 adverse events (AEs), serious AEs, and AEs of special interest were collected., Results: Three hundred forty-eight patients were enrolled at 39 US sites between June and December 2015. Patients received study therapy for a median of 1.9 months (range, 0.03-6.0 months). Fifty-two percent of patients transitioned to commercially-available daratumumab and 37% discontinued because of progressive disease. Grade ≥3 AEs occurred in 50% of patients, including thrombocytopenia (15%) and anemia (14%). Serious AEs occurred in 35% of patients (12% were drug-related), including infections (11%). Infusion reactions occurred in 56%, 2%, and 2% of patients during the first, second, and all subsequent infusions, respectively; respiratory symptoms (cough, dyspnea, throat irritation, nasal congestion) were common. The infusion reaction rate for the first infusion was 38% in 50 patients at 2 sites who received montelukast as premedication for their first infusion and 59% in patients who did not receive montelukast., Conclusions: The current findings are consistent with previously reported trials and confirm the safety profile of daratumumab in heavily pretreated US patients who have relapsed or refractory MM. Cancer 2018;124:000-000., (© 2018 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society.)
- Published
- 2018
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16. Ibrutinib alone or with dexamethasone for relapsed or relapsed and refractory multiple myeloma: phase 2 trial results.
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Richardson PG, Bensinger WI, Huff CA, Costello CL, Lendvai N, Berdeja JG, Anderson LD Jr, Siegel DS, Lebovic D, Jagannath S, Laubach JP, Stockerl-Goldstein KE, Kwei L, Clow F, Elias L, Salman Z, Graef T, Bilotti E, and Vij R
- Subjects
- Adenine analogs & derivatives, Aged, Aged, 80 and over, Antineoplastic Combined Chemotherapy Protocols adverse effects, Dexamethasone administration & dosage, Dexamethasone adverse effects, Disease-Free Survival, Female, Humans, Male, Middle Aged, Piperidines, Pyrazoles administration & dosage, Pyrazoles adverse effects, Pyrimidines administration & dosage, Pyrimidines adverse effects, Recurrence, Survival Rate, Antineoplastic Combined Chemotherapy Protocols administration & dosage, Multiple Myeloma drug therapy, Multiple Myeloma mortality
- Abstract
Novel therapies with unique new targets are needed for patients who are relapsed/refractory to current treatments for multiple myeloma. Ibrutinib is a first-in-class, once-daily, oral covalent inhibitor of Bruton tyrosine kinase, which is overexpressed in the myeloma stem cell population. This study examined various doses of ibrutinib ± low-dose dexamethasone in patients who received ≥2 prior lines of therapy, including an immunomodulatory agent. Daily ibrutinib ± weekly dexamethasone 40 mg was assessed in 4 cohorts using a Simon 2-stage design. The primary objective was clinical benefit rate (CBR; ≥minimal response); secondary objectives included safety. Patients (n = 92) received a median of 4 prior regimens. Ibrutinib + dexamethasone produced the highest CBR (28%) in Cohort 4 (840 mg + dexamethasone; n = 43), with median duration of 9·2 months (range, 3·0-14·7). Progression-free survival was 4·6 months (range, 0·4-17·3). Grade 3-4 haematological adverse events included anaemia (16%), thrombocytopenia (11%), and neutropenia (2%); grade 3-4 non-haematological adverse events included pneumonia (7%), syncope (3%) and urinary tract infection (3%). Ibrutinib + dexamethasone produced notable responses in this heavily pre-treated population. The encouraging efficacy, coupled with the favourable safety and tolerability profile of ibrutinib, supports its further evaluation as part of combination treatment., (© 2018 The Authors. British Journal of Haematology published by John Wiley & Sons Ltd.)
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- 2018
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17. Patterns of infectious complications in acute myeloid leukemia and myelodysplastic syndromes patients treated with 10-day decitabine regimen.
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Ali AM, Weisel D, Gao F, Uy GL, Cashen AF, Jacoby MA, Wartman LD, Ghobadi A, Pusic I, Romee R, Fehniger TA, Stockerl-Goldstein KE, Vij R, Oh ST, Abboud CN, Schroeder MA, Westervelt P, DiPersio JF, and Welch JS
- Subjects
- Adult, Aged, Aged, 80 and over, Antimetabolites, Antineoplastic administration & dosage, Azacitidine administration & dosage, Azacitidine adverse effects, Decitabine, Drug Administration Schedule, Female, Fever chemically induced, Fever mortality, Gram-Negative Bacterial Infections microbiology, Gram-Negative Bacterial Infections mortality, Gram-Positive Bacterial Infections microbiology, Gram-Positive Bacterial Infections mortality, Humans, Incidence, Leukemia, Myeloid, Acute diagnosis, Male, Middle Aged, Missouri, Mycoses chemically induced, Mycoses microbiology, Mycoses mortality, Myelodysplastic Syndromes diagnosis, Neutropenia chemically induced, Neutropenia mortality, Opportunistic Infections diagnosis, Opportunistic Infections microbiology, Opportunistic Infections mortality, Retrospective Studies, Risk Assessment, Risk Factors, Time Factors, Treatment Outcome, Virus Diseases chemically induced, Virus Diseases mortality, Virus Diseases virology, Antimetabolites, Antineoplastic adverse effects, Azacitidine analogs & derivatives, Gram-Negative Bacterial Infections chemically induced, Gram-Positive Bacterial Infections chemically induced, Leukemia, Myeloid, Acute drug therapy, Myelodysplastic Syndromes drug therapy, Opportunistic Infections chemically induced
- Abstract
Decitabine has been explored as a reduced-intensity therapy for older or unfit patients with acute myeloid leukemia (AML). To better understand the risk of infections during decitabine treatment, we retrospectively examined the culture results from each infection-related serious adverse event that occurred among 85 AML and myelodysplastic syndromes (MDS) patients treated in a prospective clinical study using 10-day cycles of decitabine at Washington University School of Medicine. Culture results were available for 163 infection-related complications that occurred in 70 patients: 90 (55.2%) events were culture-negative, 32 (19.6%) were gram-positive bacteria, 20 (12.3%) were gram-negative bacteria, 12 (7.4%) were mixed, 6 (3.7%) were viral, 2 (1.2%) were fungal, and 1 (0.6%) was mycobacterial. Infection-related mortality occurred in 3/24 (13%) of gram-negative events, and 0/51 gram-positive events. On average, nearly one third of patients experienced an infection-related complication with each cycle, and the incidence did not decrease during later cycles. In summary, in patients receiving 10-day decitabine, infectious complications are common and may occur during any cycle of therapy. Although febrile events are commonly culture-negative, gram-positive infections are the most frequent source of culture-positive infections, but gram-negative infections represent a significant risk of mortality in AML and MDS patients treated with decitabine., (© 2017 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)
- Published
- 2017
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18. TP53 and Decitabine in Acute Myeloid Leukemia and Myelodysplastic Syndromes.
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Welch JS, Petti AA, Miller CA, Fronick CC, O'Laughlin M, Fulton RS, Wilson RK, Baty JD, Duncavage EJ, Tandon B, Lee YS, Wartman LD, Uy GL, Ghobadi A, Tomasson MH, Pusic I, Romee R, Fehniger TA, Stockerl-Goldstein KE, Vij R, Oh ST, Abboud CN, Cashen AF, Schroeder MA, Jacoby MA, Heath SE, Luber K, Janke MR, Hantel A, Khan N, Sukhanova MJ, Knoebel RW, Stock W, Graubert TA, Walter MJ, Westervelt P, Link DC, DiPersio JF, and Ley TJ
- Subjects
- 5-Methylcytosine analysis, Adult, Aged, Aged, 80 and over, Antimetabolites, Antineoplastic adverse effects, Azacitidine administration & dosage, Azacitidine adverse effects, Biomarkers, Tumor analysis, Bone Marrow chemistry, Decitabine, Exome, Female, Humans, Leukemia, Myeloid, Acute genetics, Leukemia, Myeloid, Acute mortality, Male, Middle Aged, Myelodysplastic Syndromes genetics, Myelodysplastic Syndromes mortality, Prospective Studies, Risk Factors, Survival Rate, Antimetabolites, Antineoplastic administration & dosage, Azacitidine analogs & derivatives, Bone Marrow pathology, Leukemia, Myeloid, Acute drug therapy, Mutation, Myelodysplastic Syndromes drug therapy, Tumor Suppressor Protein p53 genetics
- Abstract
Background: The molecular determinants of clinical responses to decitabine therapy in patients with acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS) are unclear., Methods: We enrolled 84 adult patients with AML or MDS in a single-institution trial of decitabine to identify somatic mutations and their relationships to clinical responses. Decitabine was administered at a dose of 20 mg per square meter of body-surface area per day for 10 consecutive days in monthly cycles. We performed enhanced exome or gene-panel sequencing in 67 of these patients and serial sequencing at multiple time points to evaluate patterns of mutation clearance in 54 patients. An extension cohort included 32 additional patients who received decitabine in different protocols., Results: Of the 116 patients, 53 (46%) had bone marrow blast clearance (<5% blasts). Response rates were higher among patients with an unfavorable-risk cytogenetic profile than among patients with an intermediate-risk or favorable-risk cytogenetic profile (29 of 43 patients [67%] vs. 24 of 71 patients [34%], P<0.001) and among patients with TP53 mutations than among patients with wild-type TP53 (21 of 21 [100%] vs. 32 of 78 [41%], P<0.001). Previous studies have consistently shown that patients with an unfavorable-risk cytogenetic profile and TP53 mutations who receive conventional chemotherapy have poor outcomes. However, in this study of 10-day courses of decitabine, neither of these risk factors was associated with a lower rate of overall survival than the rate of survival among study patients with intermediate-risk cytogenetic profiles., Conclusions: Patients with AML and MDS who had cytogenetic abnormalities associated with unfavorable risk, TP53 mutations, or both had favorable clinical responses and robust (but incomplete) mutation clearance after receiving serial 10-day courses of decitabine. Although these responses were not durable, they resulted in rates of overall survival that were similar to those among patients with AML who had an intermediate-risk cytogenetic profile and who also received serial 10-day courses of decitabine. (Funded by the National Cancer Institute and others; ClinicalTrials.gov number, NCT01687400 .).
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- 2016
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19. Effect of Linezolid on Hematologic Recovery in Newly Diagnosed Acute Myeloid Leukemia Patients Following Induction Chemotherapy.
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Nedved AN, DeFrates SR, Hladnik LM, and Stockerl-Goldstein KE
- Subjects
- Academic Medical Centers, Adult, Anti-Bacterial Agents adverse effects, Cohort Studies, Daptomycin administration & dosage, Female, Humans, Induction Chemotherapy methods, Linezolid adverse effects, Male, Middle Aged, Neutrophils metabolism, Retrospective Studies, Time Factors, Vancomycin administration & dosage, Anti-Bacterial Agents administration & dosage, Induction Chemotherapy adverse effects, Leukemia, Myeloid, Acute drug therapy, Linezolid administration & dosage, Neutropenia chemically induced
- Abstract
Objective: Assess the effects of linezolid on hematologic outcomes in newly diagnosed patients with acute myeloid leukemia (AML) following induction chemotherapy., Design: Single-center, retrospective, observational, cohort study., Setting: Large, tertiary care academic medical center., Patients: A total of 225 patients ≥ 18 years admitted between December 2010 and 2013 with newly diagnosed AML were assessed for inclusion. Patients were identified through the use of ICD-9 codes and chemotherapy ordered via the computerized physician order entry system. Sixty-eight patients met inclusion criteria and were grouped into two arms based on antimicrobial treatment: LZD group (linezolid plus gram-negative antimicrobial, n=21) or control group (vancomycin or daptomycin plus gram-negative antimicrobial, n=47)., Interventions: The LZD group received linezolid ≥ 72 hours. The control group received vancomycin or daptomycin ≥ 72 hours. If patients switched extended gram-positive therapy, they were included in the LZD group as long as they had received ≥ 72 hours of linezolid., Measurements/results: The primary end point of time to neutrophil recovery was not statistically different (28 days for LZD group vs 26 days for control group; p=0.675). The preplanned subgroup analysis of patients who received ≥ 14 days of linezolid demonstrated statistically similar median times to neutrophil recovery (29 days for LZD group vs 26 days for control group; p=0.487). Total duration of extended gram-positive antimicrobial therapy was significantly longer in the LZD group (27 days vs 16 days; p<0.001). Secondary end points not found to be statistically significant included platelet count at time of neutrophil recovery, duration of neutropenia, and length of hospital stay., Conclusions: There were no significant differences in hematologic outcomes in newly diagnosed AML patients who received linezolid for extended gram-positive antimicrobial coverage following induction chemotherapy. This study provides new insight with a primary focus on the effects of hematologic outcomes when using linezolid in a well-defined acute leukemia population. Further study is warranted with larger populations to assess the potential adverse effects linezolid may have in patients with acute leukemia., (© 2016 Pharmacotherapy Publications, Inc.)
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- 2016
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20. Remobilization of hematopoietic stem cells in healthy donors for allogeneic transplantation.
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Fiala MA, Park S, Slade M, DiPersio JF, and Stockerl-Goldstein KE
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- Adolescent, Adult, Aged, Antigens, CD34 immunology, Benzylamines, Cyclams, Female, Granulocyte Colony-Stimulating Factor pharmacology, Hematopoietic Stem Cells drug effects, Hematopoietic Stem Cells immunology, Heterocyclic Compounds pharmacology, Humans, Leukapheresis, Male, Middle Aged, Retrospective Studies, Young Adult, Hematopoietic Stem Cell Mobilization methods, Transplantation, Homologous methods
- Abstract
Background: The need to repeat peripheral blood (PB) stem cell mobilization and collection in healthy donors arises infrequently but may be required due to insufficient initial collection, graft failure, or relapse of the recipient's disease. Little data exist on the efficacy of remobilization. Therefore, we retrospectively reviewed 18 years of remobilization records from healthy stem cell donors at our institution., Study Design and Methods: We identified 62 healthy donors who underwent remobilization, a cohort of 30 mobilized and remobilized with cytokines and a cohort of 32 mobilized with a CXCR4 antagonist and remobilized with cytokines. For each cohort we compared the PB CD34+/L level, the number of CD34+ cells collected/kg (recipient weight), and the number of CD34+ cells/L collected on the first day of leukapheresis during initial mobilization and remobilization., Results: Initial mobilization with cytokines was associated with reduced remobilization. The mean PB CD34/L level at initial mobilization was 69 × 10(6) compared to 37 × 10(6) at remobilization (p = 0.029). In contrast, initial mobilization with a CXCR4 antagonist was not associated with reduced remobilization. The mean PB CD34/L level at initial mobilization was 15 × 10(6) compared to 68 × 10(6) at remobilization (p < 0.001). In both cohorts, initial mobilization results were positively correlated with remobilization results but the interval between was not., Conclusions: This study suggests that poor remobilization yields may be due to decreased efficacy of cytokines after repeat exposure. The underlying mechanism of these findings remains unclear and further studies are needed., Competing Interests: Dr. DiPersio has received research support from AnorMED Inc, the developer of plerixafor, and Genzyme Corporation who subsequently acquired them. The author authors of no relevant disclosures., (© 2016 AABB.)
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- 2016
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21. A phase I study of carfilzomib for relapsed or refractory acute myeloid and acute lymphoblastic leukemia.
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Wartman LD, Fiala MA, Fletcher T, Hawkins ER, Cashen A, DiPersio JF, Jacoby MA, Stockerl-Goldstein KE, Pusic I, Uy GL, Westervelt P, and Vij R
- Subjects
- Antineoplastic Agents administration & dosage, Antineoplastic Agents adverse effects, Drug Resistance, Neoplasm, Humans, Oligopeptides administration & dosage, Oligopeptides adverse effects, Proteasome Inhibitors administration & dosage, Proteasome Inhibitors adverse effects, Recurrence, Retreatment, Treatment Outcome, Antineoplastic Agents therapeutic use, Leukemia, Myeloid, Acute drug therapy, Leukemia, Myeloid, Acute pathology, Oligopeptides therapeutic use, Precursor Cell Lymphoblastic Leukemia-Lymphoma drug therapy, Precursor Cell Lymphoblastic Leukemia-Lymphoma pathology, Proteasome Inhibitors therapeutic use
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- 2016
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22. Maintenance Therapy with Decitabine after Allogeneic Stem Cell Transplantation for Acute Myelogenous Leukemia and Myelodysplastic Syndrome.
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Pusic I, Choi J, Fiala MA, Gao F, Holt M, Cashen AF, Vij R, Abboud CN, Stockerl-Goldstein KE, Jacoby MA, Uy GL, Westervelt P, and DiPersio JF
- Subjects
- Adult, Aged, Allografts, Antimetabolites, Antineoplastic adverse effects, Azacitidine adverse effects, Azacitidine therapeutic use, Combined Modality Therapy, Decitabine, Disease-Free Survival, Dose-Response Relationship, Drug, Female, Gastrointestinal Diseases chemically induced, Graft vs Host Disease etiology, Hematologic Diseases chemically induced, Humans, Infusions, Intravenous, Leukemia, Myeloid, Acute therapy, Male, Maximum Tolerated Dose, Middle Aged, Myelodysplastic Syndromes therapy, Prospective Studies, Young Adult, Antimetabolites, Antineoplastic therapeutic use, Azacitidine analogs & derivatives, Hematopoietic Stem Cell Transplantation, Leukemia, Myeloid, Acute drug therapy, Maintenance Chemotherapy methods, Myelodysplastic Syndromes drug therapy
- Abstract
Decitabine is a hypomethylating agent that irreversibly inhibits DNA methyltransferase I, inducing leukemic differentiation and re-expression of epigenetically silenced putative tumor antigens. We assessed safety and efficacy of decitabine maintenance after allogeneic transplantation for acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). Decitabine maintenance may help eradicate minimal residual disease, decrease the incidence of graft-versus-host disease (GVHD), and facilitate a graft-versus-leukemia effect by enhancing the effect of T regulatory lymphocytes. Patients with AML/MDS in complete remission (CR) after allotransplantation started decitabine between day +50 and +100. We investigated 4 decitabine doses in cohorts of 4 patients: 5, 7.5, 10, and 15 mg/m(2)/day × 5 days every 6 weeks, for a maximum 8 cycles. The maximum tolerated dose (MTD) was defined as the maximum dose at which ≤ 25% of people experience dose-limiting toxicities during the first cycle of treatment. Twenty-four patients were enrolled and 22 were evaluable. All 4 dose levels were completed and no MTD was reached. Overall, decitabine maintenance was well tolerated. Grade 3 and 4 hematological toxicities were experienced by 75% of patients, including all patients treated at the highest dose level. Nine patients completed all 8 cycles and 8 of them remain in CR. Nine patients died from relapse (n = 4), infectious complications (n = 3), and GVHD (n = 2). Most occurrences of acute GVHD were mild and resolved without interruption of treatment; 1 patient died of acute gut GVHD. Decitabine maintenance did not clearly impact the rate of chronic GVHD. Although there was a trend of increased FOXP3 expression, results were not statistically significant. In conclusion, decitabine maintenance is associated with acceptable toxicities when given in the post-allotransplantation setting. Although the MTD was not reached, the dose of 10 mg/m(2) for 5 days every 6 weeks appeared to be the optimal dose rather than 15 mg/m(2), where most hematological toxicities occurred., (Copyright © 2015 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)
- Published
- 2015
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23. Hematologic Recovery after Pretransplant Chemotherapy Does Not Influence Survival after Allogeneic Hematopoietic Cell Transplantation in Acute Myeloid Leukemia Patients.
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Vu K, Manjappa S, DiPersio JF, Gao F, Westervelt P, Vij R, Stockerl-Goldstein KE, Uy GL, Abboud CN, Schroeder MA, Fehniger TA, Cashen AF, and Romee R
- Subjects
- Adolescent, Adult, Aged, Cohort Studies, Female, Hematopoietic Stem Cell Transplantation mortality, Humans, Leukemia, Myeloid, Acute mortality, Male, Middle Aged, Transplantation Conditioning mortality, Transplantation, Homologous mortality, Treatment Outcome, Young Adult, Hematologic Diseases etiology, Hematopoietic Stem Cell Transplantation methods, Leukemia, Myeloid, Acute drug therapy, Leukemia, Myeloid, Acute therapy, Transplantation Conditioning methods, Transplantation, Homologous methods
- Abstract
Pretransplant remission status in patients with acute myeloid leukemia (AML) is 1 of the most important factors determining their outcomes after allogeneic hematopoietic cell transplantation (allo-HCT). Most patients are in complete remission with full hematologic recovery (CR) before undergoing allo-HCT. However, some patients achieve CR without recovery of platelet count (CRp) or a morphologic leukemia-free state (MLFS), defined as meeting all CR criteria without recovery of both neutrophil and platelet counts. Currently, there is a paucity of data regarding transplant outcomes in AML patients achieving MLFS after chemotherapy. To address this question, we evaluated transplant outcomes in 270 AML patients who received 6/6 HLA-matched sibling or 10/10 HLA-matched unrelated donor transplantation at a single institution between 2006 and 2013. Of our 270 patients, 206 were in CR, 45 were in CRp, and 19 were in MLFS before allo-HCT. Patients in CR, CRp, or MLFS had similar 3-year overall survival rates (49%, 46%, and 47%, respectively; P = .88) and 3-year event-free survival rates (45%, 36%, and 40%, respectively; P = .53). However, the cumulative incidence of nonrelapse mortality was significantly higher in patients in MLFS compared with those in CR (58% versus 22%, P = .0004), whereas the cumulative incidence of relapse in patients in MLFS was significantly lower compared with those in CR (11% versus 36%, P = .03). Our results suggest that survival outcomes in AML patients are not influenced by degree of hematologic recovery before allo-HCT., (Copyright © 2015 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)
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- 2015
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24. Re: Disparities in Utilization of Autologous Hematopoietic Cell Transplantation for Treatment of Multiple Myeloma.
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Fiala MA, Finney JD, Stockerl-Goldstein KE, Tomasson MH, DiPersio JF, Vij R, and Wildes TM
- Subjects
- Female, Humans, Male, Hematopoietic Stem Cell Transplantation methods, Multiple Myeloma therapy
- Abstract
Costa et al. recently reported that racial disparities prevented nearly 40% of non-Hispanic blacks with multiple myeloma (MM) from undergoing stem cell transplantation (SCT), but the authors were unable to provide an explanation for the disparities because of limitations of their datasets. They hypothesized that socioeconomic status (SES) and/or insurance providers might account for the disparity. To examine the issue raised by Costa et al., we performed a secondary analysis using hierarchical multivariate logistic regression with data previously collected to determine if age at diagnosis, sex, SES, primary insurance provider at diagnosis, and comorbidity score help explain the racial disparities in SCT utilization. A model of race, age, sex, SES, insurance provider, and comorbidity score was the most accurate model in predicting stem cell utilization status (χ(2)[12] = 193.859; P < .001; area under the curve = .837; P < .001). After controlling for the covariates, black patients were less likely to undergo SCT than white patients (adjusted odds ratio, .49; 95% confidence interval, .27 to .89; P = .013). In conclusion, we also observed racial disparities between black and white patients with MM in SCT utilization and these are not fully accounted for by the covariates age, sex, SES, insurance provider, and comorbidity score., (Copyright © 2015 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)
- Published
- 2015
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25. Socioeconomic status is independently associated with overall survival in patients with multiple myeloma.
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Fiala MA, Finney JD, Liu J, Stockerl-Goldstein KE, Tomasson MH, Vij R, and Wildes TM
- Subjects
- Adult, Aged, Aged, 80 and over, Comorbidity, Female, Healthcare Disparities, Hematopoietic Stem Cell Transplantation, Humans, Insurance, Health, Male, Middle Aged, Mortality, Multiple Myeloma mortality, Multiple Myeloma therapy, Population Surveillance, Registries, Retrospective Studies, SEER Program, United States epidemiology, Multiple Myeloma epidemiology, Social Class
- Abstract
Population-based studies suggest that black patients with multiple myeloma (MM) have a higher mortality rate than white patients. However, other studies suggest that this disparity is related to socioeconomic status (SES) rather than race. To provide clarity on this topic, we reviewed 562 patients diagnosed with MM at our institution. Patients with high SES had a median overall survival (OS) of 62.8 months (95% confidence interval [CI] 43.1-82.6 months), compared to 53.7 months (45.2-62.3 months) and 48.6 months (40.4-56.8 months) for middle and low SES, respectively (p = 0.015). After controlling for race, age, year of diagnosis, severity of comorbidities, stem cell transplant utilization and insurance provider, patients with low SES had a 54% increase in mortality rate relative to patients with high SES. To support our findings, we performed a similar analysis of 45,505 patients with MM from the Surveillance, Epidemiology and End Results-18 (SEER) database. Low SES is independently associated with poorer OS in MM.
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- 2015
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26. A phase II study of V-BEAM as conditioning regimen before second auto-SCT for multiple myeloma.
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Wang TF, Fiala MA, Cashen AF, Uy GL, Abboud CN, Fletcher T, Wu N, Westervelt P, DiPersio JF, Stockerl-Goldstein KE, and Vij R
- Subjects
- Aged, Autografts, Bortezomib, Carmustine administration & dosage, Carmustine adverse effects, Cytarabine administration & dosage, Cytarabine adverse effects, Female, Follow-Up Studies, Humans, Male, Melphalan administration & dosage, Melphalan adverse effects, Middle Aged, Podophyllotoxin administration & dosage, Podophyllotoxin adverse effects, Antineoplastic Combined Chemotherapy Protocols administration & dosage, Antineoplastic Combined Chemotherapy Protocols adverse effects, Boronic Acids administration & dosage, Boronic Acids adverse effects, Multiple Myeloma mortality, Multiple Myeloma therapy, Pyrazines administration & dosage, Pyrazines adverse effects, Stem Cell Transplantation, Transplantation Conditioning adverse effects, Transplantation Conditioning methods
- Abstract
High-dose melphalan has been the standard conditioning regimen for auto-SCT in multiple myeloma (MM) for decades. A more effective conditioning regimen may induce deeper responses and longer remission duration. It is especially needed in the setting of second auto-SCT, which rarely achieves comparable results with the first auto-SCT using the same conditioning regimen. Here we conducted a phase II study to investigate the efficacy and safety of a conditioning regimen V-BEAM (bortezomib-BEAM) before second auto-SCT for multiple myeloma. Ten patients were enrolled from September 2012 to May 2013. The CR rate at day +100 after auto-SCT was 75%; all except for one patient remained in remission after a median follow-up of 6 months. Three patients developed Clostridium difficile infection. Two patients died within the first 30 days of auto-SCT from neutropenic colitis and overwhelming sepsis, respectively. Due to the high rate of morbidity and mortality, the study was terminated after 10 patients. In summary, although the conditioning regimen V-BEAM before second auto-SCT for MM provided promising responses, it was associated with unexpected treatment-related toxicity and should not be investigated further without modifications.
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- 2014
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27. A phase I dose escalation study of oral bexarotene in combination with intravenous decitabine in patients with AML.
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Welch JS, Niu H, Uy GL, Westervelt P, Abboud CN, Vij R, Stockerl-Goldstein KE, Jacoby M, Pusic I, Schroeder MA, Dipersio JF, and Cashen AF
- Subjects
- Administration, Oral, Aged, Aged, 80 and over, Animals, Azacitidine therapeutic use, Bexarotene, Decitabine, Drug Administration Schedule, Drug Therapy, Combination, Female, Gene Expression, Gene Expression Profiling, Humans, Injections, Intravenous, Leukemia, Promyelocytic, Acute genetics, Leukemia, Promyelocytic, Acute metabolism, Leukemia, Promyelocytic, Acute pathology, Male, Mice, Middle Aged, Receptors, Retinoic Acid genetics, Receptors, Retinoic Acid metabolism, Recurrence, Retinoic Acid Receptor alpha, Retinoid X Receptor alpha genetics, Retinoid X Receptor alpha metabolism, Tumor Cells, Cultured, Anticarcinogenic Agents therapeutic use, Antimetabolites, Antineoplastic therapeutic use, Azacitidine analogs & derivatives, Leukemia, Promyelocytic, Acute drug therapy, Tetrahydronaphthalenes therapeutic use
- Abstract
The response rate of non-M3 acute myeloid leukemia (AML) to all trans retinoic acid has been limited. Using Affymetrix expression arrays, we found that in diverse AML blasts RXRA was expressed at higher levels than RARA and that mouse Ctsg-PML-RARA leukemia responded to bexarotene, a ligand for RXRA. We therefore performed a phase I study of combination bexarotene and decitabine in elderly and relapsed AML patients. We found that this combination was well tolerated, although outcomes were modest (1 CRi, and 3 PR among 19 patients). Correlative studies found that patients with clinical response had increased differentiation to bexarotene both in vivo and ex vivo, suggesting that pre-treatment analysis might identify a more susceptible subgroup of patients., (© 2014 Wiley Periodicals, Inc.)
- Published
- 2014
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28. The characteristics and outcomes of patients with multiple myeloma dual refractory or intolerant to bortezomib and lenalidomide in the era of carfilzomib and pomalidomide.
- Author
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Wang TF, Ahluwalia R, Fiala MA, Trinkaus KM, Cox DP, Jaenicke M, Moliske CC, Carson KR, Wildes TM, Tomasson MH, Stockerl-Goldstein KE, and Vij R
- Subjects
- Adult, Aged, Boronic Acids administration & dosage, Bortezomib, Drug Resistance, Neoplasm, Drug Tolerance, Female, Humans, Lenalidomide, Logistic Models, Male, Middle Aged, Multivariate Analysis, Oligopeptides administration & dosage, Outcome Assessment, Health Care, Prognosis, Pyrazines administration & dosage, Retrospective Studies, Risk Factors, Survival Analysis, Thalidomide administration & dosage, Thalidomide analogs & derivatives, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Multiple Myeloma drug therapy
- Abstract
Patients with multiple myeloma who are refractory or intolerant to both bortezomib and lenalidomide have a poor prognosis. Next-generation therapies carfilzomib and pomalidomide have shown promising activity in this dual refractory population. Here we describe the clinical characteristics and ascertain the effects of carfilzomib and pomalidomide on survival in this patient cohort. We retrospectively reviewed the records of 65 patients with dual refractory/intolerant myeloma diagnosed between January 2007 and May 2012 at a single institution. The median overall survival (OS) from the time patients became dual refractory/intolerant was 10.2 months. Patients who received carfilzomib or pomalidomide after they became dual refractory/intolerant had a better OS compared to those who did not (12.6 vs. 6.8 months, p = 0.03 by Wilcoxon test). Prospective randomized control trials are needed for confirmation.
- Published
- 2014
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29. Oral valganciclovir versus ganciclovir as delayed pre-emptive therapy for patients after allogeneic hematopoietic stem cell transplant: a pilot trial (04-0274) and review of the literature.
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Chawla JS, Ghobadi A, Mosley J 3rd, Verkruyse L, Trinkaus K, Abboud CN, Cashen AF, Stockerl-Goldstein KE, Uy GL, Westervelt P, DiPersio JF, and Vij R
- Subjects
- Administration, Oral, Adolescent, Adult, Antiviral Agents administration & dosage, Cytomegalovirus drug effects, Cytomegalovirus Infections virology, Dose-Response Relationship, Drug, Female, Ganciclovir administration & dosage, Humans, Male, Middle Aged, Pilot Projects, Polymerase Chain Reaction, Prospective Studies, Transplantation, Homologous, Valganciclovir, Viral Load drug effects, Viremia virology, Young Adult, Antiviral Agents therapeutic use, Cytomegalovirus Infections prevention & control, Ganciclovir analogs & derivatives, Ganciclovir therapeutic use, Hematopoietic Stem Cell Transplantation, Viremia prevention & control
- Abstract
Background: Cytomegalovirus (CMV) infection is an important cause of morbidity and mortality after allogeneic hematopoietic stem cell transplant (HSCT). This pilot prospective randomized clinical trial compares valganciclovir (VGV) to ganciclovir (GCV) as pre-emptive therapy for CMV viremia in the post-allogeneic HSCT population., Methods: Patients undergoing allogeneic HSCT who were at risk for CMV viremia were monitored post HSCT by weekly quantitative whole blood polymerase chain reaction. Pre-emptive therapy was delayed until the viral load (VL) was >10,000 copies/mL once, or >5000 copies/mL twice. Patients were randomized to either GCV 5 mg/kg twice a day (b.i.d.) for 7 days followed by daily GCV 5 mg/kg for up to 21 days, or VGV 900 mg b.i.d. for 7 days followed by 900 mg daily for up to 21 days. The primary endpoint was clearance of viremia (VL <5000 copies/mL) within 28 days of initiation of therapy., Result: In total, 37 patients were enrolled; 19 patients received treatment with VGV and 18 patients received treatment with GCV. The VGV was not inferior in efficacy to GCV as pre-emptive therapy, with rates of viral clearance at 28 days of 89.5% and 83%, respectively (P-value for non-inferiority = 0.030). Toxicities were similar between the 2 arms. No patients developed CMV disease., Conclusions: In this trial, the rates of clearance of viremia appear to be similar with VGV and GCV., (© 2011 John Wiley & Sons A/S.)
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- 2012
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30. A phase 1/2 study of chemosensitization with the CXCR4 antagonist plerixafor in relapsed or refractory acute myeloid leukemia.
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Uy GL, Rettig MP, Motabi IH, McFarland K, Trinkaus KM, Hladnik LM, Kulkarni S, Abboud CN, Cashen AF, Stockerl-Goldstein KE, Vij R, Westervelt P, and DiPersio JF
- Subjects
- Adolescent, Adult, Aged, Benzylamines, Cyclams, Cytarabine administration & dosage, Etoposide administration & dosage, Female, Flow Cytometry, Humans, Male, Middle Aged, Mitoxantrone administration & dosage, Prognosis, Remission Induction, Survival Rate, Young Adult, Anti-HIV Agents therapeutic use, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Drug Resistance, Neoplasm, Heterocyclic Compounds therapeutic use, Leukemia, Myeloid, Acute drug therapy, Neoplasm Recurrence, Local drug therapy, Receptors, CXCR4 antagonists & inhibitors, Salvage Therapy
- Abstract
The interaction of acute myeloid leukemia (AML) blasts with the leukemic microenvironment is postulated to be an important mediator of resistance to chemotherapy and disease relapse. We hypothesized that inhibition of the CXCR4/CXCL12 axis by the small molecule inhibitor, plerixafor, would disrupt the interaction of leukemic blasts with the environment and increase the sensitivity of AML blasts to chemotherapy. In this phase 1/2 study, 52 patients with relapsed or refractory AML were treated with plerixafor in combination with mitoxantrone, etoposide, and cytarabine. In phase 1, plerixafor was escalated to a maximum of 0.24 mg/kg/d without any dose-limiting toxicities. In phase 2, 46 patients were treated with plerixafor 0.24 mg/kg/d in combination with chemotherapy with an overall complete remission and complete remission with incomplete blood count recovery rate (CR + CRi) of 46%. Correlative studies demonstrated a 2-fold mobilization in leukemic blasts into the peripheral circulation. No evidence of symptomatic hyperleukocytosis or delayed count recovery was observed with the addition of plerixafor. We conclude that the addition of plerixafor to cytotoxic chemotherapy is feasible in AML, and results in encouraging rates of remission with correlative studies demonstrating in vivo evidence of disruption of the CXCR4/CXCL12 axis.
- Published
- 2012
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31. Long-term outcome of patients with metastatic breast cancer treated with high-dose chemotherapy and transplantation of purified autologous hematopoietic stem cells.
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Müller AM, Kohrt HE, Cha S, Laport G, Klein J, Guardino AE, Johnston LJ, Stockerl-Goldstein KE, Hanania E, Juttner C, Blume KG, Negrin RS, Weissman IL, and Shizuru JA
- Subjects
- Adult, Breast Neoplasms pathology, Cohort Studies, Combined Modality Therapy, Disease-Free Survival, Female, Humans, Middle Aged, Neoplasm Metastasis, Retrospective Studies, Survival Analysis, Transplantation, Autologous, Treatment Outcome, Breast Neoplasms drug therapy, Breast Neoplasms surgery, Hematopoietic Stem Cell Transplantation methods
- Abstract
Metastatic breast cancer remains a major treatment challenge. The use of high-dose chemotherapy (HDCT) with rescue by autologous mobilized peripheral blood (MPB) is controversial, in part because of contamination of MPB by circulating tumor cells. CD34(+)Thy-1(+) selected hematopoietic stem cells (HSC) represent a graft source with a greater than 250,000-fold reduction in cancer cells. Here, we present the long-term outcome of a pilot study to determine feasibility and engraftment using HDCT and purified HSC in patients with metastatic breast cancer. Twenty-two patients who had been treated with standard chemotherapy were enrolled into a phase I/II trial between December 1996 and February 1998, and underwent HDCT followed by rescue with CD34(+)Thy-1(+) HSC isolated from autologous MPB. More than 12 years after the end of the study, 23% (5 of 22) of HSC recipients are alive, and 18% (4 of 22) are free of recurrence with normal hematopoietic function. Median progression-free survival (PFS) was 16 months, and median overall survival (OS) was 60 months. Retrospective comparison with 74 patients transplanted between February 1995 and June 1999 with the identical HDCT regimen but rescue with unmanipulated MPB indicated that 9% of patients are alive, and 7% are without disease. Median PFS was 10 months, and median OS was 28 months. In conclusion, cancer-depleted HSC following HDCT resulted in better than expected 12- to 14-year PFS and OS in a cohort of metastatic breast cancer patients. These data prompt us to look once again at purified HSC transplantation in a protocol powered to test for efficacy in advanced-stage breast cancer patients., (Copyright © 2012 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)
- Published
- 2012
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32. Prognostic significance of FDG-PET in relapsed or refractory classical Hodgkin lymphoma treated with standard salvage chemotherapy and autologous stem cell transplantation.
- Author
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Smeltzer JP, Cashen AF, Zhang Q, Homb A, Dehdashti F, Abboud CN, Dipersio JF, Stockerl-Goldstein KE, Uy GL, Vij R, Westervelt P, Bartlett NL, and Fehniger TA
- Subjects
- Adolescent, Adult, Aged, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Disease-Free Survival, Female, Follow-Up Studies, Hodgkin Disease drug therapy, Hodgkin Disease surgery, Humans, Male, Middle Aged, Prognosis, Prospective Studies, Recurrence, Transplantation, Autologous methods, Young Adult, Fluorodeoxyglucose F18, Hematopoietic Stem Cell Transplantation methods, Hodgkin Disease diagnostic imaging, Hodgkin Disease therapy, Positron-Emission Tomography methods, Salvage Therapy methods
- Abstract
Positron emission tomography using [(18)F]fluorodeoxyglucose (FDG-PET) has emerged as the standard response assessment tool in frontline therapy for classical Hodgkin lymphoma (cHL). The ability of FDG-PET to predict outcomes in patients with relapsed cHL treated with modern standard salvage chemotherapy and autologous stem cell transplantation (ASCT) remains uncertain. Forty-six patients with relapsed/refractory cHL treated from 2001 to 2007 with standard salvage/ASCT therapy had FDG-PET available for blinded review. The results of pre-ASCT FDG-PET interpreted by the international harmonization project (IHP) criteria were compared with published prognostic models for prediction of event-free survival (EFS) and overall survival (OS). Overall, 3-year EFS was 62% and OS was 78%, with a median follow-up of 38 months. Pre-ASCT FDG-PET response significantly predicted 3-year EFS in FDG-PET-negative (82%) versus FDG-PET-positive (41%) patients (P = .02). A trend was observed for 3-year OS comparing FDG-PET-negative (91%) versus -positive (64%) patients (P = .08). Multivariate analysis demonstrated the independent prognostic significance of pre-ASCT FDG-PET for EFS with a hazard ratio (HR) of 3.2 (confidence interval [CI] 1.1-9.0, P = .03). Pre-ASCT FDG-PET scans predict EFS in patients with relapsed cHL patients treated with modern salvage/ASCT therapy and warrant prospective evaluation., (Copyright © 2011 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)
- Published
- 2011
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33. Combination decitabine, arsenic trioxide, and ascorbic acid for the treatment of myelodysplastic syndrome and acute myeloid leukemia: a phase I study.
- Author
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Welch JS, Klco JM, Gao F, Procknow E, Uy GL, Stockerl-Goldstein KE, Abboud CN, Westervelt P, DiPersio JF, Hassan A, Cashen AF, and Vij R
- Subjects
- Adult, Aged, Angiogenesis Inhibitors administration & dosage, Angiogenesis Inhibitors adverse effects, Angiogenesis Inhibitors pharmacology, Angiogenesis Inhibitors therapeutic use, Antineoplastic Agents adverse effects, Antineoplastic Agents pharmacology, Antineoplastic Agents therapeutic use, Antineoplastic Combined Chemotherapy Protocols adverse effects, Antineoplastic Combined Chemotherapy Protocols pharmacology, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Arsenic Trioxide, Arsenicals adverse effects, Arsenicals pharmacology, Arsenicals therapeutic use, Ascorbic Acid adverse effects, Ascorbic Acid pharmacology, Ascorbic Acid therapeutic use, Azacitidine administration & dosage, Azacitidine adverse effects, Azacitidine pharmacology, Azacitidine therapeutic use, Bone Marrow blood supply, Bone Marrow drug effects, Bone Marrow Cells drug effects, Bone Marrow Cells metabolism, Cohort Studies, Decitabine, Dose-Response Relationship, Drug, Female, Gene Expression Profiling, Humans, Leukemia, Myeloid, Acute metabolism, Male, Middle Aged, Myelodysplastic Syndromes metabolism, Neovascularization, Pathologic drug therapy, Oxides adverse effects, Oxides pharmacology, Oxides therapeutic use, Young Adult, Antineoplastic Agents administration & dosage, Antineoplastic Combined Chemotherapy Protocols administration & dosage, Arsenicals administration & dosage, Ascorbic Acid administration & dosage, Azacitidine analogs & derivatives, Leukemia, Myeloid, Acute drug therapy, Myelodysplastic Syndromes drug therapy, Oxides administration & dosage
- Published
- 2011
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34. A phase 2 study of high-dose lenalidomide as initial therapy for older patients with acute myeloid leukemia.
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Fehniger TA, Uy GL, Trinkaus K, Nelson AD, Demland J, Abboud CN, Cashen AF, Stockerl-Goldstein KE, Westervelt P, DiPersio JF, and Vij R
- Subjects
- Age Factors, Aged, Aged, 80 and over, Antineoplastic Agents adverse effects, Blood Cell Count, Cytogenetic Analysis, Disease-Free Survival, Female, Humans, Kaplan-Meier Estimate, Lenalidomide, Leukemia, Myeloid, Acute blood, Leukemia, Myeloid, Acute genetics, Male, Middle Aged, Prognosis, Prospective Studies, Remission Induction, Thalidomide administration & dosage, Thalidomide adverse effects, Time Factors, Treatment Outcome, Antineoplastic Agents administration & dosage, Leukemia, Myeloid, Acute drug therapy, Thalidomide analogs & derivatives
- Abstract
Older patients with acute myeloid leukemia (AML) have limited treatment options and a poor prognosis, thereby warranting novel therapeutic strategies. We evaluated the efficacy of lenalidomide as front-line therapy for older AML patients. In this phase 2 study, patients 60 years of age or older with untreated AML received high-dose (HD) lenalidomide at 50 mg daily for up to 2 28-day cycles. If patients achieved a complete remission (CR)/CR with incomplete blood count recovery (CRi) or did not progress after 2 cycles of HD lenalidomide, they received low-dose lenalidomide (10 mg daily) until disease progression, an unacceptable adverse event, or completion of 12 cycles. Thirty-three AML patients (median age, 71 years) were enrolled with intermediate (55%), unfavorable (39%), or unknown (6%) cytogenetic risk. Overall CR/CRi rate was 30%, and 53% in patients completing HD lenalidomide. The CR/CRi rate was significantly higher in patients presenting with a low (< 1000/μL) circulating blast count (50%, P = .01). The median time to CR/CRi was 30 days, and duration of CR/CRi was 10 months (range, 1- ≥ 17 months). The most common grades ≥ 3 toxicities were thrombocytopenia, anemia, infection, and neutropenia. HD lenalidomide has evidence of clinical activity as initial therapy for older AML patients, and further study of lenalidomide in AML and MDS is warranted. This study is registered at www.clinicaltrials.gov as #NCT00546897.
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- 2011
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35. A meta-analysis of patients receiving allogeneic or autologous hematopoietic stem cell transplant in mycosis fungoides and Sézary syndrome.
- Author
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Wu PA, Kim YH, Lavori PW, Hoppe RT, and Stockerl-Goldstein KE
- Subjects
- Adult, Female, Graft vs Host Disease, Graft vs Tumor Effect, Hematopoietic Stem Cell Transplantation methods, Hematopoietic Stem Cell Transplantation mortality, Humans, Male, Middle Aged, Mycosis Fungoides mortality, Sezary Syndrome mortality, Survival Analysis, Transplantation, Autologous, Transplantation, Homologous, Young Adult, Hematopoietic Stem Cell Transplantation statistics & numerical data, Mycosis Fungoides therapy, Sezary Syndrome therapy
- Abstract
The survival outlook in advanced mycosis fungoides (MF) is poor. Autologous and allogeneic stem cell transplants (SCT) have been shown, in small case series and case reports, to have the potential for long-term remission or to alter disease course. Allogeneic SCT is thought to have a curative potential secondary to a graft-versus-lymphoma (GVL) effect. A patient-level meta-analysis was performed to compare the outcome of allogeneic versus autologous SCT in patients with MF/Sézary syndrome (SS) using 39 cases from the literature. There were a total of 20 allogeneic and 19 autologous transplant cases. The gender, age, and stage distribution was similar between the transplant groups. The allogeneic group received significantly more systemic therapies prior to transplant (P < .0005) and had longer follow-up after transplant. Overall survival (OS) results showed a more favorable outcome of patients who received allogeneic SCT (P = .027). Event-free survival (EFS) demonstrated a more durable response in patients who received allogeneic SCT (P = .002). In the allogeneic group, the majority (70%) of patients experienced persistent graft-versus-host disease (GVHD), mostly with mild to moderate severity, and 2 of 4 deaths were related to GVHD. Meanwhile, the majority of the deaths (8 of 10) in the autologous group were because of progressive disease. These results support the belief that allogeneic SCT offers a better survival and disease-free outcome versus autologous SCT in MF/SS, likely because of a GVL effect.
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- 2009
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36. High-dose chemotherapy followed by stem cell rescue for high-risk germ cell tumors: the Stanford experience.
- Author
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Agarwal R, Dvorak CC, Stockerl-Goldstein KE, Johnston L, and Srinivas S
- Subjects
- Adolescent, Adult, Antineoplastic Combined Chemotherapy Protocols administration & dosage, Carboplatin administration & dosage, Child, Combined Modality Therapy, Cyclophosphamide administration & dosage, Disease-Free Survival, Etoposide administration & dosage, Female, Hematopoietic Stem Cell Mobilization, Hematopoietic Stem Cells pathology, Humans, Male, Middle Aged, Neoplasms, Germ Cell and Embryonal drug therapy, Hematopoietic Stem Cell Transplantation, Neoplasms, Germ Cell and Embryonal therapy
- Abstract
Germ cell tumors carry an excellent prognosis with platinum-based therapy upfront. The patients who either relapse or demonstrate refractoriness to platinum pose a challenge. There exist many reports in the literature on the use of high-dose chemotherapy and stem cell rescue improving the outcome in patients with relapsed germ cell tumors. However, the reports have great variability in the patient selection, prior treatments, the choice of the conditioning regimen and variability of the doses within the same regimen. In this report, we present 37 patients who underwent a uniform protocol of high-dose chemotherapy with stem cell rescue. Stem cell mobilization was performed with high-dose CY (4 g per m(2)) and we were able to collect adequate cells for marrow rescue in all patients. Patients received a high-dose regimen with etoposide (800 mg/m(2) per day) days -6, -5 and -4 as a continuous infusion, carboplatin (667 mg/m(2) per day) on days -6, -5 and -4 as a 1 h infusion, and CY (60 mg/kg per day) on days -3 and -2. In this high-risk group of patients, high-dose chemotherapy with autologous stem cell rescue led to a 3-year overall survival of 57% and a 3-year event-free survival of 49%. The results are reflective of a single procedure. No tandem transplants were performed. The treatment-related mortality was low at 3% in this heavily pretreated group.
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- 2009
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37. Impact of mobilization and remobilization strategies on achieving sufficient stem cell yields for autologous transplantation.
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Pusic I, Jiang SY, Landua S, Uy GL, Rettig MP, Cashen AF, Westervelt P, Vij R, Abboud CN, Stockerl-Goldstein KE, Sempek DS, Smith AL, and DiPersio JF
- Subjects
- Antigens, CD34, Benzylamines, Cyclams, Female, Hematologic Neoplasms therapy, Humans, Leukocyte Count, Male, Middle Aged, Recombinant Proteins, Retrospective Studies, Transplantation, Autologous, Anti-HIV Agents administration & dosage, Blood Component Removal methods, Granulocyte Colony-Stimulating Factor administration & dosage, Hematopoietic Stem Cell Mobilization methods, Hematopoietic Stem Cells, Heterocyclic Compounds administration & dosage, Stem Cell Transplantation
- Abstract
The purpose of this article was to examine historic institutional autologous stem cell mobilization practices and evaluate factors influencing mobilization failure and kinetics. In this retrospective study we analyzed clinical records of 1834 patients who underwent stem cell mobilization for autologous transplantation from November 1995 to October 2006 at the Washington University in St. Louis. Successful mobilization was defined as collection of > or =2 x 10(6) CD34(+) cells/kg. From 1834 consecutive patients, 1040 met our inclusion criteria (502 non-Hodgkin's lymphoma [NHL], 137 Hodgkin's lymphoma, and 401 multiple myeloma [MM]). A total of 976 patients received granulocyte colony-stimulating factor (G-CSF) and 64 received G-CSF plus chemotherapy (G/C) for the initial mobilization. Although the median CD34(+) cell yield was higher in G/C group than in G-CSF alone group, the failure rates were similar: 18.8% and 18.6%, respectively. Overall, 53% of patients collected > or =2 x 10(6) CD34(+) cells/kg during the first apheresis with either mobilization regimen. Regardless of mobilization regimen used, MM patients had the highest total CD34(+) cell yield and required less aphereses to collect > or =2 x 10(6) CD34(+) cells/kg. Mobilized, preapheresis, peripheral blood CD34(+) count correlated with first day apheresis yield (r = .877, P < .001) and 20 cells/microL was the minimum threshold needed for a successful day 1 collection. For the remobilization analysis we included patients from the whole database. A total of 269 of 1834 patients underwent remobilization using G/C, G-CSF, and/or GM-CSF, and G-CSF plus plerixafor. Only 23% of remobilized patients achieved > or =2 x 10(6) CD34(+) cells/kg and 29.7% failed to pool sufficient number of stem cells from both collections. Patients receiving G-CSF plus plerixafor had lowest failure rates, P = .03. NHL patients remobilized with G-CSF who waited > or =25 days before remobilization had lower CD34(+) cell yield than those who waited < or =16 days, P = .023. Current mobilization regimens are associated with a substantial failure rate irrespective of underlying disease. Patients who fail initial mobilization are more likely to fail remobilization. These findings suggest that there is a need for more effective first-line mobilization agents.
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- 2008
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38. High-dose carmustine, etoposide, and cyclophosphamide followed by allogeneic hematopoietic cell transplantation for non-Hodgkin lymphoma.
- Author
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Law LY, Horning SJ, Wong RM, Johnston LJ, Laport GG, Lowsky R, Shizuru JA, Blume KG, Negrin RS, and Stockerl-Goldstein KE
- Subjects
- Adult, Antineoplastic Combined Chemotherapy Protocols administration & dosage, Carmustine administration & dosage, Cause of Death, Combined Modality Therapy methods, Cyclophosphamide administration & dosage, Etoposide administration & dosage, Female, Graft vs Host Disease mortality, Histocompatibility Testing, Humans, Lymphoma, Non-Hodgkin mortality, Male, Middle Aged, Survival Analysis, Transplantation, Homologous methods, Treatment Outcome, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Hematopoietic Stem Cell Transplantation methods, Lymphoma, Non-Hodgkin therapy, Transplantation Conditioning methods
- Abstract
Allogeneic hematopoietic cell transplantation (HCT) has been shown to be curative in a group of patients with aggressive non-Hodgkin lymphoma (NHL). A previous study has demonstrated equivalent outcomes with a conditioning regimen based on total body irradiation and another not based on total body irradiation with preparative therapy using cyclophosphamide, carmustine, and etoposide (CBV) in autologous HCT. We investigated the safety and efficacy of using CBV in an allogeneic setting. Patients were required to have relapsed or be at high risk for subsequent relapse of NHL. All patients had a fully HLA-matched sibling donor. Patients received carmustine (15 mg/kg), etoposide (60 mg/kg), and cyclophosphamide (100 mg/kg) on days -6, -4, and -2, respectively, followed by allogeneic HCT. All patients were treated with cyclosporine and methylprednisolone as prophylaxis for graft-versus-host disease (GVHD). Thirty-one patients (median age, 46 years) who were felt to be inappropriate candidates for autologous transplantation were enrolled. Each subject had a median of 3 previous chemotherapy regimens. All patients engrafted. Fifteen of 31 patients are alive. Median follow-up time was 11.5 months (range, .4-126). There were 8 deaths due to relapse. Nonrelapse mortality (n = 8) included infection (n = 3), GVHD (n = 2), diffuse alveolar hemorrhage (n = 1), veno-occlusive disease in the setting of concurrent acute GVHD of the liver (n = 1), and leukoencephalopathy (n = 1). Probabilities of event-free survival and overall survival were, respectively, 44% (95% confidence interval, 26%-62%) and 51% (33%-69%) at 1 year and 44% (26%-62%) and 47% (29%-65%) at 5 years. Probability of relapse was 33% (15%-51%) at 1 year and 5 years. Probability of nonrelapse mortality was 31% (13%-49%) at 1 year and 5 years. Incidences were 29% for acute GVHD and 39% for chronic GVHD. None of the 12 patients who developed chronic GVHD has disease recurrence. Patients who had required >3 previous chemotherapy regimens before HCT had an increased probability of relapse. CBV is an effective preparative regimen for patients with aggressive NHL who undergo allogeneic HCT.
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- 2006
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39. Engraftment and survival following reduced-intensity allogeneic peripheral blood hematopoietic cell transplantation is affected by CD8+ T-cell dose.
- Author
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Cao TM, Shizuru JA, Wong RM, Sheehan K, Laport GG, Stockerl-Goldstein KE, Johnston LJ, Stuart MJ, Grumet FC, Negrin RS, and Lowsky R
- Subjects
- Adult, Aged, Antigens, CD, Chronic Disease, Disease-Free Survival, Female, Follow-Up Studies, Graft vs Host Disease etiology, Graft vs Host Disease mortality, Granulocyte-Macrophage Colony-Stimulating Factor administration & dosage, Hematologic Neoplasms therapy, Hematopoietic Stem Cell Mobilization, Histocompatibility Testing, Humans, Male, Middle Aged, Myeloablative Agonists, Recombinant Proteins, Survival Rate, Transplantation Chimera, Transplantation, Homologous, Treatment Outcome, Vidarabine administration & dosage, Vidarabine analogs & derivatives, Whole-Body Irradiation, CD8-Positive T-Lymphocytes transplantation, Graft Survival radiation effects, Hematologic Neoplasms mortality, Peripheral Blood Stem Cell Transplantation mortality, Transplantation Conditioning mortality
- Abstract
The influence of graft composition on clinical outcomes after reduced-intensity conditioning is not well-characterized. In this report we prospectively enumerated CD34+, CD3+, CD4+, and CD8+ cell doses in granulocyte colony-stimulating factor-mobilized peripheral blood mononuclear cell (G-PBMC) allografts in 63 patients who received transplants following non-myeloablative conditioning with total body irradiation 200 cGy plus fludarabine as treatment for malignant diseases. Donors were HLA-identical siblings (n = 38) or HLA-matched unrelated individuals (n = 25). By univariate analyses G-PBMC CD8+ T-cell dose in at least the 50th percentile favorably correlated with full donor blood T-cell chimerism (P = .03), freedom from progression (P = .001), and overall survival (P = .01). No G-PBMC cell dose influenced grade II to IV acute or extensive chronic graft-versus-host disease. In multivariate analysis only G-PBMC CD8+ T-cell dose (P = .003; RR = 0.2, 95% CI = 0.1-0.6) was associated with improved freedom from progression. Infusion of low G-PBMC CD8+ T-cell dose for reduced-intensity allografting may adversely affect T-cell engraftment and survival outcome.
- Published
- 2005
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40. CD34, CD4, and CD8 cell doses do not influence engraftment, graft-versus-host disease, or survival following myeloablative human leukocyte antigen-identical peripheral blood allografting for hematologic malignancies.
- Author
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Cao TM, Wong RM, Sheehan K, Laport GG, Stockerl-Goldstein KE, Johnston LJ, Shizuru JA, Negrin RS, and Lowsky R
- Subjects
- Adult, Aged, Antigens, Surface, Female, Hematologic Neoplasms mortality, Humans, Male, Middle Aged, Retrospective Studies, Transplantation Conditioning, Transplantation, Homologous, Graft Survival, Graft vs Host Disease, Hematologic Neoplasms therapy, Peripheral Blood Stem Cell Transplantation
- Abstract
Objectives: Optimal granulocyte colony-stimulating factor-mobilized peripheral blood progenitor cell (G-PBMC) graft compositions for myeloablative allogeneic hematopoietic cell transplantation (AHCT) have not been identified. G-PBMC cell contents were analyzed for influence on outcomes., Patients and Methods: Human leukocyte antigen(HLA)-identical related donor AHCT was used to treat 101 patients with hematologic malignancies at a single institution between 1995 and 2002. CD34+, CD3+, CD4+, and CD8+ cell doses were enumerated by flow cytometry and evaluated by univariate analysis., Results: Categorized by the median of cell doses infused, no G-PBMC cell dose significantly correlated with neutrophil and platelet engraftment. Incidence of grade II to IV acute graft-versus-host disease (GVHD) was 24.6% (95% confidence interval [CI]: 15.9-33.3) and was not significantly influenced by evaluated G-PBMC cell doses. With a median follow-up time of 18 months for surviving patients, estimates for extensive chronic GVHD was 43.8% (95% CI: 31.4-56.2), for freedom from progression was 69.5% (95% CI: 58.1-80.9), and for overall survival was 46.9% (95% CI: 35.5-58.3). CD34+, CD3+, CD4+, and CD8+ cell doses were not significantly predictive of extensive chronic GVHD, freedom from progression or overall survival. Additionally, comparing patients receiving the upper versus lower 33rd percentiles of CD34+ cell dose, associations with extensive chronic GVHD remained insignificant (p=0.21; relative risk (RR)=1.7; 95% CI: 0.7-3.9)., Conclusions: G-PBMC graft content does not influence outcomes after myeloablative AHCT. In particular, no significant association between extensive chronic GVHD was identified with any G-PBMC cell dose, including CD34.
- Published
- 2005
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41. Rapamycin (sirolimus) for treatment of chronic graft-versus-host disease.
- Author
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Johnston LJ, Brown J, Shizuru JA, Stockerl-Goldstein KE, Stuart MJ, Blume KG, Negrin RS, and Chao NJ
- Subjects
- Adult, Calcineurin Inhibitors, Cause of Death, Chronic Disease, Creatinine blood, Drug Therapy, Combination, Graft vs Host Disease complications, Hematopoietic Stem Cell Transplantation adverse effects, Hemolytic-Uremic Syndrome chemically induced, Humans, Middle Aged, Patient Compliance, Prednisone administration & dosage, Recurrence, Sirolimus toxicity, Treatment Outcome, Graft vs Host Disease drug therapy, Sirolimus administration & dosage
- Abstract
We conducted a phase II trial in 19 chronic graft-versus-host disease (cGVHD) patients with rapamycin, calcineurin inhibitors, and prednisone with the goals of controlling cGVHD, reducing prednisone use, and defining the safety of this regimen. Rapamycin was begun as second-line (n = 9) or more than second-line (n = 10) therapy. With a median follow-up of 42 months, 16 patients were evaluable for response. Nine patients discontinued rapamycin because of poor compliance/patient request (n = 2) or an adverse event (n = 7), 3 of whom were not evaluable because of withdrawal at < or =1 month or noncompliance. The adverse events included serum creatinine > or =2.4 mg/dL (n = 4), hemolytic uremic syndrome (n = 2), and relapse of malignancy (n = 1). Fifteen of 16 evaluable patients had a clinical response. Five of the 16 discontinued the drug, and 1 died of relapsed leukemia. Of the 10 patients who continued rapamycin, 2 discontinued and 1 successfully tapered all systemic immunosuppression. Three of the 10 developed progressive cGVHD with tapering immunosuppression; all responded to resumption of prior medications. Four of the 10 patients required alternate therapy for persistent or progressive cGVHD while receiving rapamycin; prednisone was discontinued (n = 2) or tapered at the time of progressive disease (n = 2). Seventeen of 19 original patients were alive. One death was due to relapsed malignancy, and 1 was due to congestive heart failure. In this report of rapamycin as cGVHD therapy, there is evidence of rapamycin's efficacy. Given the significant toxicities described, investigation of altered administration of rapamycin and calcineurin inhibitors should be pursued in future cGVHD trials.
- Published
- 2005
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42. A randomized trial of amifostine and carmustine-containing chemotherapy to assess lung-protective effects.
- Author
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Jones RB, Stockerl-Goldstein KE, Klein J, Murphy J, Blume KG, Dansey R, Martinez C, Matthes S, and Nieto Y
- Subjects
- Adult, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Breast Neoplasms therapy, Carmustine therapeutic use, Cisplatin therapeutic use, Cyclophosphamide therapeutic use, Double-Blind Method, Female, Hematopoietic Stem Cell Transplantation, Humans, Middle Aged, Placebos administration & dosage, Respiratory Distress Syndrome chemically induced, Respiratory Distress Syndrome diagnosis, Treatment Outcome, Amifostine administration & dosage, Antineoplastic Agents, Alkylating administration & dosage, Antineoplastic Combined Chemotherapy Protocols adverse effects, Carmustine administration & dosage, Carmustine adverse effects, Cisplatin adverse effects, Cyclophosphamide adverse effects, Radiation-Protective Agents administration & dosage, Respiratory Distress Syndrome prevention & control
- Abstract
We conducted a randomized, double blind, placebo-controlled multi-institutional trial to assess the ability of amifostine to protect patients against acute lung injury associated with cyclophosphamide/cisplatin/carmustine (BCNU) (STAMP I), a BCNU-containing high dose chemotherapy regimen used with hematopoietic cell transplantation. Amifostine was administered in a dose of 740 mg/m(2) for 2 doses preceding administration of BCNU, the presumed pulmonary-toxic component of the regimen. The trial was stopped after 79 patients were randomized and a planned interim analysis demonstrated that it was unlikely that pulmonary cytoprotection would be detected with further accrual. We conclude that amifostine, used in the dose and schedule we tested, does not reduce the incidence of acute lung injury produced by STAMP I. Further, we suggest that amifostine use with BCNU in other contexts and with clinically achievable doses is unlikely to protect the lung from BCNU-associated acute injury.
- Published
- 2004
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43. Rituximab as adjuvant to high-dose therapy and autologous hematopoietic cell transplantation for aggressive non-Hodgkin lymphoma.
- Author
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Horwitz SM, Negrin RS, Blume KG, Breslin S, Stuart MJ, Stockerl-Goldstein KE, Johnston LJ, Wong RM, Shizuru JA, and Horning SJ
- Subjects
- Adult, Aged, Antibodies, Monoclonal adverse effects, Antibodies, Monoclonal, Murine-Derived, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Combined Modality Therapy, Disease-Free Survival, Female, Hematopoietic Stem Cell Transplantation, Humans, Lymphoma, B-Cell drug therapy, Lymphoma, B-Cell mortality, Male, Middle Aged, Prospective Studies, Rituximab, Survival Rate, Transplantation, Autologous, Antibodies, Monoclonal therapeutic use, Lymphoma, B-Cell therapy
- Abstract
Based on the favorable safety profile and the independent activity of rituximab in B-cell lymphoma, we evaluated its efficacy and toxicity after high-dose therapy (HDT) and autologous hematopoietic cell transplantation (HCT). Thirty-five patients with diffuse large cell (25 patients), mantle cell (3 patients), transformed (3 patients), or other (4 patients) subtypes of B-cell lymphoma received HDT followed by a purged autologous graft. The rituximab schedule was 4 weekly infusions (375 mg/m(2)) starting at day 42 after HCT and, for patients 5 to 35, a second 4-week course 6 months after HCT. All planned therapy was completed in 29 patients. With 30 months' median follow-up, the 2-year event-free survival (EFS) rate was 83% and the overall survival (OS) rate was 88%. For 21 patients with relapsed or refractory large cell lymphoma, the EFS rate was 81% and the OS rate was 85%. Grades 3 to 4 neutropenia occurred in 19 (54%) patients. A prospective study of immune reconstitution included measurements of lymphocyte subsets, immunoglobulins, and response to vaccination. Serious infections were not observed despite delayed B-cell recovery in all patients and suppressed immunoglobulin G (IgG) levels and low pneumococcus antibody titers in a subset. Rituximab after HDT and HCT is feasible, and these phase 2 data support the current US Intergroup phase 3 trial in recurrent/refractory diffuse large cell lymphoma.
- Published
- 2004
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44. Allografting with nonmyeloablative conditioning following cytoreductive autografts for the treatment of patients with multiple myeloma.
- Author
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Maloney DG, Molina AJ, Sahebi F, Stockerl-Goldstein KE, Sandmaier BM, Bensinger W, Storer B, Hegenbart U, Somlo G, Chauncey T, Bruno B, Appelbaum FR, Blume KG, Forman SJ, McSweeney P, and Storb R
- Subjects
- Adult, Aged, Antineoplastic Agents therapeutic use, Antineoplastic Agents toxicity, Female, Hematopoietic Stem Cell Transplantation adverse effects, Hematopoietic Stem Cell Transplantation mortality, Humans, Immunosuppressive Agents therapeutic use, Immunosuppressive Agents toxicity, Male, Middle Aged, Multiple Myeloma complications, Multiple Myeloma mortality, Survival Analysis, Transplantation Conditioning mortality, Transplantation, Autologous methods, Transplantation, Homologous methods, Transplantation, Isogeneic, Treatment Outcome, Hematopoietic Stem Cell Transplantation methods, Multiple Myeloma therapy, Transplantation Conditioning methods
- Abstract
The full potential of a graft-versus-myeloma effect after allogeneic hematopoietic cell transplantation (HCT) for patients with multiple myeloma (MM) has not been realized because of excessive early transplantation-related mortality (TRM) with conventional HCT. Autologous HCTs have been characterized by almost universal disease recurrences. The current trial combined autologous HCT with subsequent nonmyeloablative allogeneic HCT to maintain the benefits of both approaches with acceptable toxicity. Fifty-four patients, 52 years of age (median; range, 29-71 years), with previously treated stage II or III MM (52% refractory or relapsed disease) were given melphalan 200 mg/m2 and autologous HC transplants. Regimen-related toxicities after autologous HCT were moderate with a median of 6 days of neutropenia, 7 days of hospitalization, and 1 death from infection. Forty to 229 days later (median, 62 days), 52 patients received a single fraction dose of 2 Gy total body irradiation and HC transplants from HLA-identical siblings with postgrafting immunosuppression with mycophenolate mofetil (MMF) and cyclosporine (CSP). Patients experienced medians of 0 days of hospitalization, neutropenia, and thrombocytopenia. Sustained engraftment was uniform. With a median follow-up of 552 days after allografting, overall survival is 78%. One patient (2%) died before day 100 from disease progression. Thirty-eight percent of patients developed acute graft-versus-host disease (GVHD; grade II in all but 4 cases) and 46% chronic GVHD requiring therapy. Tumor responses occurred slowly. Thus far, 57% of patients have achieved complete remissions and 26% have achieved partial remissions for an overall response of 83%. Despite being evaluated in elderly patients with MM, this 2-step approach has reduced the acute toxicities of allogeneic HCT while achieving potent antitumor activities.
- Published
- 2003
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45. Rapid establishment of dendritic cell chimerism in allogeneic hematopoietic cell transplant recipients.
- Author
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Auffermann-Gretzinger S, Lossos IS, Vayntrub TA, Leong W, Grumet FC, Blume KG, Stockerl-Goldstein KE, Levy R, and Shizuru JA
- Subjects
- Adult, Aged, Blood Cells cytology, Blood Cells immunology, Dendritic Cells immunology, Female, Graft Survival physiology, Hematologic Neoplasms therapy, Hematopoiesis, Humans, Immune System cytology, Immune System growth & development, Kinetics, Lymphocyte Culture Test, Mixed, Male, Middle Aged, Transplantation Conditioning, Transplantation, Homologous, Dendritic Cells cytology, Hematopoietic Stem Cell Transplantation, Transplantation Chimera immunology
- Abstract
Regeneration of hematopoiesis after allogeneic hematopoietic cell transplantation (HCT) involves conversion of the recipient's immune system to donor type. It is likely that distinct cell lineages in the recipient reconstitute at different rates. Dendritic cells (DCs) are a subset of hematopoietic cells that function as a critical component of antigen-specific immune responses because they modulate T-cell activation, as well as induction of tolerance. Mature DCs are transferred with hematopoietic grafts and subsequently arise de novo. Little information exists about engraftment kinetics and turnover of this cell population in patients after allogeneic HCT. This study examined the kinetics of DC chimerism in patients who underwent matched sibling allogeneic HCT. T-cell, B-cell, and myelocytic and monocytic chimerism were also studied. Peripheral blood cells were analyzed at defined intervals after transplantation from 19 patients with various hematologic malignancies after treatment with myeloablative or nonmyeloablative preparatory regimens. Cell subsets were isolated before analysis of chimerism. Despite the heterogeneity of the patient population and preparatory regimens, all showed rapid and consistent development of DC chimerism. By day +14 after transplantation approximately 80% of DCs were of donor origin with steady increase to more than 95% by day +56. Earlier time points were examined in a subgroup of patients who had undergone nonmyeloablative conditioning and transplantation. These data suggest that a major proportion of blood DCs early after transplantation is donor-derived and that donor chimerism develops rapidly. This information has potential implications for manipulation of immune responses after allogeneic HCT.
- Published
- 2002
- Full Text
- View/download PDF
46. Rapid engraftment after allogeneic transplantation of density-enriched peripheral blood CD34+ cells in patients with advanced hematologic malignancies.
- Author
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Cao TM, Kusnierz-Glaz C, Valone F, Stockerl-Goldstein KE, Hu WW, Johnston L, Blume KG, Strober S, and Negrin RS
- Subjects
- Adult, Centrifugation, Density Gradient, Female, Flow Cytometry, Graft vs Host Disease prevention & control, Hematopoietic Stem Cell Mobilization methods, Humans, Leukemia, Myelogenous, Chronic, BCR-ABL Positive therapy, Leukemia, Myeloid, Acute therapy, Lymphoma, Non-Hodgkin therapy, Male, Middle Aged, Multiple Myeloma therapy, Myelodysplastic Syndromes therapy, Precursor Cell Lymphoblastic Leukemia-Lymphoma therapy, Transplantation, Homologous, Treatment Outcome, Antigens, CD34 analysis, Cell Separation methods, Hematopoietic Stem Cell Transplantation, Leukemia therapy, Lymphoma therapy, T-Lymphocytes immunology
- Abstract
Background: Acute graft versus host disease (GVHD) remains a major cause of morbidity and mortality after allogeneic hematopoietic cell transplantation. Preclinical studies have suggested that a T-cell subset with a CD4-/CD8- double-negative (DN) T-cell phenotype is capable of suppressing GVHD. Double-negative T cells can be mobilized into the peripheral blood with granulocyte colony-stimulating factor (G-CSF) and enriched by density centrifugation. The current study was performed to study the feasibility and safety of applying a density gradient separation technique for enrichment of CD34+ and DN T cells, while depleting CD4+ and CD8+ single-positive (SP) T cells from peripheral blood progenitor cells (PBPCs) for the purpose of allogeneic transplantation., Methods: Twenty-five patients with advanced hematologic malignancies were treated with a myeloablative preparative regimen consisting of fractionated total body irradiation, etoposide, and cyclophosphamide. Human leukocyte antigen identical donors were mobilized with G-CSF PBPC collected by apheresis. The apheresis product was applied to a single-step density gradient, and the low-density cell population was collected. The low-density cell population was infused as the sole source of allogeneic cells after myeloablative therapy. Graft versus host disease prophylaxis consisted of cyclosporine with or without prednisone., Results: CD34 cell recovery was efficient with a median 72% yield, providing for a median CD34+ cell dose of 6.5 x 10(6)/kg (range,1.0- 13.9 x 10(6)/kg). CD3+CD4+ or CD3+CD8+ SP T cells were depleted by a median of 94.4% (range, 58.8- 99.2%), and the ratio of CD34+:SP T cells increased 10-fold. Double-negative T cells were depleted by 92% (range, 18.8- 99.4%), thus the ratio of DN:SP T cells increased less than 2-fold in 71% of apheresis samples tested. Hematopoietic engraftment was rapid, and there was no occurrence of graft failure in examinable patients. Median time to absolute neutrophil count greater than 0.5 x 10(9)/L and platelet count greater than 20 x 10(9)/L was 10.5 and 12 days, respectively. The incidence of Grade 2-4 acute GVHD was 26% (95% confidence interval [CI], 6-45%), although not all patients were examinable due to an unexpectedly high nonrecurrence mortality that at Day 180 was 62% (95% CI, 40-83%)., Conclusions: These data suggest that T-cell subset manipulation via density gradient separation is a safe procedure and allowed rapid hematopoietic recovery. Selective enrichment of a donor DN T-cell subset was observed in only a few and was not associated with a reduced incidence of GVHD. However, the low-density selected cells still resulted in GVHD, and there was a high treatment-related mortality., (Copyright 2001 American Cancer Society.)
- Published
- 2001
47. A decade of progress in allogeneic hematopoietic cell transplantation: 1990-2000.
- Author
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Stockerl-Goldstein KE and Blume KG
- Subjects
- Anemia therapy, Graft vs Host Disease prevention & control, Hematopoietic Stem Cell Transplantation adverse effects, Humans, Leukemia therapy, Lymphoma therapy, Transplantation, Homologous adverse effects, Hematopoietic Stem Cell Transplantation methods, Transplantation, Homologous methods
- Published
- 2001
- Full Text
- View/download PDF
48. Efficacy and toxicity of a CCNU-containing high-dose chemotherapy regimen followed by autologous hematopoietic cell transplantation in relapsed or refractory Hodgkin's disease.
- Author
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Stuart MJ, Chao NS, Horning SJ, Wong RM, Negrin RS, Johnston LJ, Shizuru JA, Long GD, Blume KG, and Stockerl-Goldstein KE
- Subjects
- Adolescent, Adult, Aged, Antineoplastic Agents, Alkylating toxicity, Antineoplastic Combined Chemotherapy Protocols administration & dosage, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Carmustine administration & dosage, Carmustine toxicity, Child, Cyclophosphamide administration & dosage, Dose-Response Relationship, Drug, Etoposide administration & dosage, Female, Hodgkin Disease complications, Humans, Lomustine toxicity, Lung Diseases, Interstitial chemically induced, Lymphoma, Non-Hodgkin complications, Lymphoma, Non-Hodgkin therapy, Male, Maximum Tolerated Dose, Middle Aged, Salvage Therapy adverse effects, Salvage Therapy methods, Salvage Therapy mortality, Stem Cell Transplantation adverse effects, Stem Cell Transplantation mortality, Survival Rate, Therapeutic Equivalency, Transplantation, Autologous, Antineoplastic Agents, Alkylating administration & dosage, Hodgkin Disease therapy, Lomustine administration & dosage, Stem Cell Transplantation methods
- Abstract
High-dose CBV (cyclophosphamide, carmustine, and etoposide) in combination with autologous HCT achieves survival rates of approximately 50% at 5 years in recurrent or refractory Hodgkin's disease (HD). However, carmustine (BCNU) dose-dependent pulmonary toxicity occurs in 20% to 30% of patients. A decreased incidence of interstitial pneumonitis as well as a possible benefit in efficacy has been reported with lomustine (CCNU) compared to BCNU in the standard dose setting. In a dose-escalation study, we substituted CCNU for BCNU in the CBV regimen for 16 patients with HD (n = 12) or non-Hodgkin's lymphoma (n = 4). Based on the promising results, an additional 47 consecutive patients with HD were treated with the following regimen: CCNU (15 mg/kg) orally on day -6, etoposide (60 mg/kg) intravenously on day -4, and cyclophosphamide (100 mg/kg) intravenously on day -2. Peripheral blood progenitor cells and/or bone marrow were infused on day 0. With a median follow-up for the surviving patients of 3.2 years (range, 0.8-9.9 years), the 3-year overall survival rate was 57% (CI, +/-15%), event-free survival was 52% (CI, +/-14%), and freedom from progression was 68% (CI, +/-14%). There were 21 deaths, 10 due to HD. Six patients died due to respiratory failure. Interstitial pneumonitis occurred in 63% of patients and could not be correlated with prior chest radiotherapy. This regimen demonstrated survival rates similar to those of historical studies that used the CBV regimen. However, the incidence of interstitial pneumonitis was in excess of expected.
- Published
- 2001
- Full Text
- View/download PDF
49. High-dose therapy and autologous hematopoietic-cell transplantation for follicular lymphoma beyond first remission: the Stanford University experience.
- Author
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Cao TM, Horning S, Negrin RS, Hu WW, Johnston LJ, Taylor TL, Shizuru JA, Hoppe RT, Brown BW, Blume KG, and Stockerl-Goldstein KE
- Subjects
- Adult, Aged, Carmustine administration & dosage, Combined Modality Therapy, Cyclophosphamide administration & dosage, Disease-Free Survival, Etoposide administration & dosage, Female, Humans, Lymphoma, Follicular classification, Lymphoma, Follicular complications, Male, Middle Aged, Neural Tube Defects etiology, Prognosis, Recurrence, Remission Induction, Retrospective Studies, Survival Analysis, Transplantation, Autologous, Treatment Outcome, Whole-Body Irradiation, Antineoplastic Combined Chemotherapy Protocols administration & dosage, Hematopoietic Stem Cell Transplantation, Lymphoma, Follicular therapy
- Abstract
A retrospective analysis was performed to investigate the outcome of high-dose therapy (HDT) and autologous hematopoietic cell transplantation in patients with follicular lymphomas beyond first remission. Ninety-two patients with primary induction failure or relapsed follicular low-grade lymphoma (FLGL), follicular large cell lymphoma (FLCL), and transformed follicular lymphoma (TFL) were treated with myeloablative therapy consisting of etoposide (60 mg/kg), cyclophosphamide (100 mg/kg), and either carmustine (BCNU;15 mg/kg) or fractionated total body irradiation (FTBI; 1200 cGy) followed by transplantation of purged autologous bone marrow or peripheral blood hematopoietic cells. For the 49 patients with relapsed FLGL, the median age was 49 years and the median interval from diagnosis to HDT was 30 months. The 4-year estimate of overall survival (OS) was 60% (95% confidence interval [CI], 45%-75%) and of disease-free survival (DFS) was 44% (95% CI, 29%-59%). Treatment with the FTBI-containing HDT regimen was associated with significantly longer DFS (P = .04) and OS (P = .04) in our multivariate analysis. OS was also significantly longer among those treated with 3 or fewer chemotherapy regimens. For the 26 FLCL patients, the median age was 51 years and in 31% the indication for HDT was primary induction failure. For FLCL patients, the 4-year estimate of OS was 58% (95% CI, 37%-79%) and of DFS was 51% (95% CI, 30%-72%). Among the 17 patients with TFL, 13 (76%) transformed at first relapse, and only 6 patients (35%) achieved complete remission with salvage therapy prior to HDT. For TFL patients, the 4-year estimate of OS was 50% (95% CI, 24%-76%) and of DFS 49% (95% CI, 20%-78%). There were 3 occurrences of myelodysplasia (1 after treatment with TBI, 2 after BCNU treatment), yielding an estimated incidence of 7% (95% CI, 0%-16%) at 56 months. This analysis shows that relapsed FLGL patients treated with 3 or fewer different chemotherapy regimens show inferior survival. The HDT regimen containing FTBI appears to be superior to the BCNU-based regimen for relapsed FLGL, although longer follow-up is needed to evaluate late effects. Lastly, patients with TFL or induction failure and relapsed FLCL can achieve survival outcome comparable to those observed with the indolent follicular lymphomas.
- Published
- 2001
- Full Text
- View/download PDF
50. Effect of oral glutamine supplementation during bone marrow transplantation.
- Author
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Coghlin Dickson TM, Wong RM, offrin RS, Shizuru JA, Johnston LJ, Hu WW, Blume KG, and Stockerl-Goldstein KE
- Subjects
- Administration, Oral, Adolescent, Adult, Double-Blind Method, Female, Glutamine administration & dosage, Humans, Length of Stay, Male, Middle Aged, Nutritional Status, Bone Marrow Transplantation, Glutamine therapeutic use, Leukemia therapy, Parenteral Nutrition, Total
- Abstract
Background: Because all patients receiving bone marrow transplant (BMT) and peripheral blood progenitor cell transplant (PBPCT) experience gastrointestinal (GI) toxicity from the preparative regimen of chemotherapy, with or without radiation, oral glutamine was administered during the preparatory regimen and after transplant to maintain GI structure and function., Methods: To evaluate effects of oral glutamine on nutritional status and overall outcome, a prospective, randomized, double-blinded study was performed on 58 autologous and allogeneic BMT patients. Patients received 30 g of oral glutamine or placebo daily., Results: The trends of decreased median length of stay and the median number of days of total parenteral nutrition (TPN) were seen in the group supplemented with the >0.285-g/kg (the recommended dosage) dose of glutamine; however, there was no statistically significant difference in the nutritional status and overall patient outcome as assessed by days receiving TPN, number of days required until oral intake resumed, length of hospitalization, number of days and highest grade of mucositis, and quantity and number of days of diarrhea., Conclusions: This study does not support the hypothesis that oral glutamine may offer benefit. Further investigation is required regarding clinical tools for determining effectiveness, administration for tolerance and compliance, dosage, and potential of oral glutamine usage.
- Published
- 2000
- Full Text
- View/download PDF
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