285 results on '"Joseph O. Moore"'
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2. Design and rationale for the life after stopping tyrosine kinase inhibitors (LAST) study, a prospective, single-group longitudinal study in patients with chronic myeloid leukemia
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Ehab Atallah, Charles A. Schiffer, Kevin P. Weinfurt, Mei-Jie Zhang, Jerald P. Radich, Vivian G. Oehler, Javier Pinilla-Ibarz, Michael W. N. Deininger, Li Lin, Richard A. Larson, Michael J. Mauro, Joseph O. Moore, Ellen K. Ritchie, Neil P. Shah, Richard T. Silver, Martha Wadleigh, Jorge Cortes, James Thompson, Jessica Guhl, Mary M. Horowitz, and Kathryn E. Flynn
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Chronic myeloid leukemia ,Oncology ,Targeted therapy ,Tyrosine kinase inhibitor ,Discontinuation ,Clinical trial ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract Background Treatment of chronic myeloid leukemia with a tyrosine kinase inhibitor (TKI) offers significant improvements over previous treatments in terms of survival and toxicity yet nevertheless is associated with reduced health-related quality of life and very high cost. Several small studies from Europe and Australia suggested that discontinuing TKIs with regular monitoring was safe. Methods The Life After Stopping TKIs (LAST) study is a large, U.S.-based study that aims to improve the evidence for clinical decision making regarding TKI discontinuation with monitoring in patients with chronic myeloid leukemia who have a deep molecular response to TKI therapy. The LAST study is a non-randomized, prospective, single-group longitudinal study of 173 patients. The co-primary objectives are to determine the proportion of patients who develop molecular recurrence (> 0.1% BCR-ABLIS) after discontinuing one of four TKIs (imatinib, dasatinib, nilotinib, or bosutinib) and to compare the patient-reported health status of patients before and after stopping TKIs. Outcomes are assessed at baseline and throughout the 36-month study follow-up period with a central laboratory used for blood samples. All samples with undetectable BCR-ABL are also examined using digital polymerase chain reaction, which is a more sensitive nanofluidic polymerase chain reaction system. Discussion Because of their high cost and side effects, discontinuation of TKIs for patients with chronic myeloid leukemia who have a deep molecular response to TKI therapy is a promising approach to treatment. The LAST study is the largest U.S.-based TKI discontinuation study. It is the first to allow participation from patients on any of 4 first- and second-generation TKIs, includes a robust approach to measurement of clinical and patient-reported outcomes, and is using digital polymerase chain reaction to explore better prediction of safe discontinuation. Trial registration This study was registered prospectively on October 21, 2014 and assigned trial number NCT02269267.
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- 2018
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3. In rare acute myeloid leukemia patients harboring both RUNX1 and NPM1 mutations, RUNX1 mutations are unusual in structure and present in the germline
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Jason H. Mendler, Kati Maharry, Heiko Becker, Ann-Kathrin Eisfeld, Leigha Senter, Krzysztof Mrózek, Jessica Kohlschmidt, Klaus H. Metzeler, Sebastian Schwind, Susan P. Whitman, Jihane Khalife, Michael A. Caligiuri, Rebecca B. Klisovic, Joseph O. Moore, Thomas H. Carter, Guido Marcucci, and Clara D. Bloomfield
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Published
- 2013
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4. Clinical outcome and gene- and microRNA-expression profiling according to the Wilms tumor 1 (WT1) single nucleotide polymorphism rs16754 in adult de novo cytogenetically normal acute myeloid leukemia: a Cancer and Leukemia Group B study
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Heiko Becker, Kati Maharry, Michael D. Radmacher, Krzysztof Mrózek, Klaus H. Metzeler, Susan P. Whitman, Sebastian Schwind, Jessica Kohlschmidt, Yue-Zhong Wu, Bayard L. Powell, Thomas H. Carter, Jonathan E. Kolitz, Meir Wetzler, Andrew J. Carroll, Maria R. Baer, Joseph O. Moore, Michael A. Caligiuri, Richard A. Larson, Guido Marcucci, and Clara D. Bloomfield
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
Background The alleles of the Wilms tumor 1 (WT1) polymorphism rs16754 harbor adenine (A) or guanine (G). Recently, rs16754 has been reported to affect the outcome of patients with cytogenetically normal acute myeloid leukemia. To validate this finding, we investigated pretreatment features and outcome associated with rs16754 in a large cohort of patients with cytogenetically normal acute myeloid leukemia.Design and Methods Four-hundred and thirty-three intensively treated and molecularly characterized cytogenetically normal patients with de novo acute myeloid leukemia (18–83 years old) were analyzed for rs16754. To gain biological insights, we studied the gene- and microRNA-expression profiles for associations with rs16754.Results Three-hundred and nine (71%) patients were homozygous for A (WT1AA), 112 (26%) were heterozygous (WT1AG) and 12 (3%) were homozygous for G (WT1GG). For comparison with previous studies, we grouped WT1AG and WT1GG patients and compared them with WT1AA patients divided into younger (
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- 2011
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5. Sex-Associated Differences in Frequencies and Outcome Prognostication of Recurrent Molecular Features in Adults with Acute Myeloid Leukemia (AML) (AMLCG, CALGB [Alliance])
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Michael P. Ozga, Deedra Nicolet, Krzysztof Mrózek, Selen Yilmaz, Jessica Kohlschmidt, Karilyn T. Larkin, James S. Blachly, Christopher C. Oakes, Jill Buss, Christopher J. Walker, Shelley Orwick, Vindi Jurinovic, Maja Rothenberg-Thurley, Annika Maria Dufour, Stephanie Schneider, Maria Cristina Sauerland, Dennis Görlich, Utz Krug, Wolfgang E. Berdel, Bernhard Josef Woermann, Wolfgang Hiddemann, Jan Braess, Marion Subklewe, Karsten Spiekermann, Andrew J. Carroll, William G. Blum, Bayard L. Powell, Jonathan E. Kolitz, Joseph O. Moore, Robert James Mayer, Richard M. Stone, Geoffrey L. Uy, Wendy Stock, Klaus H. Metzeler, H. Leighton Grimes, John C. Byrd, Nathan Salomonis, Tobias Herold, Alice S. Mims, and Ann-Kathrin Eisfeld
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Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
6. High early death rates, treatment resistance, and short survival of Black adolescents and young adults with AML
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Karilyn T. Larkin, Deedra Nicolet, Benjamin J. Kelly, Krzysztof Mrózek, Stephanie LaHaye, Katherine E. Miller, Saranga Wijeratne, Gregory Wheeler, Jessica Kohlschmidt, James S. Blachly, Alice S. Mims, Christopher J. Walker, Christopher C. Oakes, Shelley Orwick, Isaiah Boateng, Jill Buss, Adrienne Heyrosa, Helee Desai, Andrew J. Carroll, William Blum, Bayard L. Powell, Jonathan E. Kolitz, Joseph O. Moore, Robert J. Mayer, Richard A. Larson, Richard M. Stone, Electra D. Paskett, John C. Byrd, Elaine R. Mardis, and Ann-Kathrin Eisfeld
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Adult ,Proto-Oncogene Proteins p21(ras) ,Cytogenetics ,Leukemia, Myeloid, Acute ,Young Adult ,Adolescent ,Drug Resistance, Neoplasm ,Antineoplastic Combined Chemotherapy Protocols ,Remission Induction ,Black People ,Humans ,Hematology - Abstract
Survival of patients with acute myeloid leukemia (AML) is inversely associated with age, but the impact of race on outcomes of adolescent and young adult (AYA; range, 18-39 years) patients is unknown. We compared survival of 89 non-Hispanic Black and 566 non-Hispanic White AYA patients with AML treated on frontline Cancer and Leukemia Group B/Alliance for Clinical Trials in Oncology protocols. Samples of 327 patients (50 Black and 277 White) were analyzed via targeted sequencing. Integrated genomic profiling was performed on select longitudinal samples. Black patients had worse outcomes, especially those aged 18 to 29 years, who had a higher early death rate (16% vs 3%; P=.002), lower complete remission rate (66% vs 83%; P=.01), and decreased overall survival (OS; 5-year rates: 22% vs 51%; P
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- 2022
7. Supplementary Data from A Genomic Approach to Improve Prognosis and Predict Therapeutic Response in Chronic Lymphocytic Leukemia
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Joseph R. Nevins, Anil Potti, Carlos M. Decastro, Louis F. Diehl, Jon P. Gockerman, Joseph O. Moore, Ning Jiang, Youwei Chen, Karen M. Bond, Alicia D. Volkheimer, Barbara K. Goodman, William T. Barry, J. Brice Weinberg, and Daphne R. Friedman
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Supplementary Data from A Genomic Approach to Improve Prognosis and Predict Therapeutic Response in Chronic Lymphocytic Leukemia
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- 2023
8. Data from A Genomic Approach to Improve Prognosis and Predict Therapeutic Response in Chronic Lymphocytic Leukemia
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Joseph R. Nevins, Anil Potti, Carlos M. Decastro, Louis F. Diehl, Jon P. Gockerman, Joseph O. Moore, Ning Jiang, Youwei Chen, Karen M. Bond, Alicia D. Volkheimer, Barbara K. Goodman, William T. Barry, J. Brice Weinberg, and Daphne R. Friedman
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Purpose: Chronic lymphocytic leukemia (CLL) is a B-cell malignancy characterized by a variable clinical course. Several parameters have prognostic capabilities but are associated with altered response to therapy in only a small subset of patients.Experimental Design: We used gene expression profiling methods to generate predictors of therapy response and prognosis. Genomic signatures that reflect progressive disease and responses to chemotherapy or chemoimmunotherapy were created using cancer cell lines and patient leukemia cell samples. We validated and applied these three signatures to independent clinical data from four cohorts, representing a total of 301 CLL patients.Results: A genomic signature of prognosis created from patient leukemic cell gene expression data coupled with clinical parameters significantly differentiated patients with stable disease from those with progressive disease in the training data set. The progression signature was validated in two independent data sets, showing a capacity to accurately identify patients at risk for progressive disease. In addition, genomic signatures that predict response to chlorambucil or pentostatin, cyclophosphamide, and rituximab were generated and could accurately distinguish responding and nonresponding CLL patients.Conclusions: Thus, microarray analysis of CLL lymphocytes can be used to refine prognosis and predict response to different therapies. These results have implications for standard and investigational therapeutics in CLL patients. (Clin Cancer Res 2009;15(22):694755)
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- 2023
9. Genomic Integration of Adult and Pediatric Acute Myeloid Leukemia Reveals Age Dependent Risk Association
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Maarten Fornerod, Deedra Nicolet, Krzysztof Mrózek, Jonathan E. Kolitz, William G. Blum, Joseph O. Moore, Robert James Mayer, Richard M. Stone, Geoffrey L. Uy, Wendy Stock, John C. Byrd, Ann-Kathrin Eisfeld, and Tanja A. Gruber
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Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
10. Chronic Myeloid Leukemia, Version 2.2021, NCCN Clinical Practice Guidelines in Oncology
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B. Douglas Smith, Monica Mead, Michal G. Rose, Jessica K. Altman, Leland Metheny, Ravi Bhatia, Michael W. Deininger, Mrinal M. Patnaik, Moshe Talpaz, Joseph O. Moore, Kendra Sweet, Kiran Naqvi, Lori J. Maness, Arnel Pallera, Sanjay R. Mohan, Gabriela S. Hobbs, Bhavana Bhatnagar, James E. Thompson, Daniel J. DeAngelo, Kristina M. Gregory, Keith W. Pratz, David T. Yang, Ellin Berman, Neil P. Shah, Hema Sundar, David S. Snyder, Jason Gotlib, Iskra Pusic, and Vivian G. Oehler
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business.industry ,medicine.drug_class ,Fusion Proteins, bcr-abl ,Myeloid leukemia ,Treatment options ,Chromosomal translocation ,Medical Oncology ,Blast Phase ,Philadelphia chromosome ,medicine.disease ,Translocation, Genetic ,Tyrosine-kinase inhibitor ,Fusion gene ,Oncology ,Leukemia, Myelogenous, Chronic, BCR-ABL Positive ,hemic and lymphatic diseases ,Leukemia, Myeloid, Chronic-Phase ,Cancer research ,Humans ,Medicine ,Philadelphia Chromosome ,Chronic phase CML ,business - Abstract
Chronic myeloid leukemia (CML) is defined by the presence of Philadelphia chromosome (Ph) which results from a reciprocal translocation between chromosomes 9 and 22 [t(9;22] that gives rise to aBCR-ABL1fusion gene. CML occurs in 3 different phases (chronic, accelerated, and blast phase) and is usually diagnosed in the chronic phase. Tyrosine kinase inhibitor therapy is a highly effective first-line treatment option for all patients with newly diagnosed chronic phase CML. This manuscript discusses the recommendations outlined in the NCCN Guidelines for the diagnosis and management of patients with chronic phase CML.
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- 2020
11. Phase II Study of Single-Agent and Combination Everolimus and Panobinostat in Relapsed or Refractory Diffuse Large B-Cell Lymphoma
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David A. Rizzieri, Zhiguo Li, Louis F. Diehl, Anne W. Beaven, Tod A. Morris, Chenyu Lin, Carlos M. de Castro, Prioty Islam, and Joseph O. Moore
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Adult ,Male ,Cancer Research ,Combination therapy ,Phases of clinical research ,chemistry.chemical_compound ,Refractory ,Recurrence ,hemic and lymphatic diseases ,Panobinostat ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Refractory Diffuse Large B-Cell Lymphoma ,Humans ,Everolimus ,Prospective Studies ,Aged ,Aged, 80 and over ,business.industry ,General Medicine ,Middle Aged ,medicine.disease ,Lymphoma ,Oncology ,chemistry ,Cancer research ,Female ,Lymphoma, Large B-Cell, Diffuse ,business ,Diffuse large B-cell lymphoma ,medicine.drug - Abstract
Novel therapeutics are needed for patients with relapsed or refractory diffuse large B-cell lymphoma (R/R DLBCL). Everolimus is an mTOR pathway inhibitor with synergistic anti-tumor activity when combined with histone deacetylase inhibitors, such as panobinostat, in preclinical lymphoma models. In this Phase II study, we evaluated overall response rate to single and combination everolimus and panobinostat in R/R DLBCL. Fifteen patients were enrolled to single-agent and 18 to combination. One patient responded to everolimus, while none responded to panobinostat. Though 25% of patients responded to combination therapy, responses were not durable with significant toxicity. We demonstrated minimal single-agent activity and prohibitive toxicity with combination therapy.
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- 2021
12. Phase I Study of the Combination of Bendamustine, Rituximab, and Pixantrone in Patients With Relapsed/Refractory B-cell Non-Hodgkin Lymphoma
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Anne W. Beaven, David J. Adams, Benjamin Heyman, Joseph O. Moore, David A. Rizzieri, Carlos M. de Castro, Zhiguo Li, and Louis F. Diehl
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Adult ,Male ,0301 basic medicine ,Bendamustine ,Cancer Research ,medicine.medical_specialty ,Lymphoma, B-Cell ,Maximum Tolerated Dose ,Anthracycline ,Neutropenia ,Gastroenterology ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Refractory ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Bendamustine Hydrochloride ,Humans ,Prospective Studies ,Aged ,Aged, 80 and over ,Salvage Therapy ,Pixantrone ,business.industry ,Hematology ,Middle Aged ,Isoquinolines ,Prognosis ,medicine.disease ,Lymphoma ,Survival Rate ,Regimen ,030104 developmental biology ,Oncology ,chemistry ,Drug Resistance, Neoplasm ,030220 oncology & carcinogenesis ,Female ,Rituximab ,Neoplasm Recurrence, Local ,business ,Follow-Up Studies ,medicine.drug - Abstract
Background For patients with aggressive lymphomas who relapse after initial therapy, a durable response is rarely achieved with standard salvage therapies. Significant efforts have focused on the development of novel treatments with reduced toxicity. We conducted a phase I prospective single arm clinical trial of the novel combination of BuRP (bendamustine, rituximab, and pixantrone) in patients with relapsed/refractory (R/R) aggressive B-cell non-Hodgkin lymphoma (NHL). Patients and Methods Eligible patients included adults with biopsy-proven R/R B-cell NHL who met the criteria for treatment. Patients received bendamustine 120 mg/m2, rituximab 375 mg/m2, and pixantrone, per cohort dose, on day 1 for up to 6 cycles. Dose escalation used a 3 + 3 design, from a starting dose level of pixantrone 55 mg/m2 to 115 mg/m at dose level 3. Results Twenty-two patients were enrolled onto the study with a median follow-up of 7.9 months. The maximum tolerated dose was not reached, but the highest dose level of pixantrone of 115 mg/m2 was well-tolerated. The most common grade 3/4 adverse events were neutropenia (27%) and thrombocytopenia (23%). The mean change in left ventricular ejection fraction was 2.5% (standard deviation, 5.51%; 95% confidence interval, 0.0%-4.9%). The overall response rate for the entire cohort was 37.5% (95% confidence interval, 15%-65%), but at the highest pixantrone dose, the overall response rate was 63%, with a complete response rate of 25%. Conclusion The BuRP regimen was found to be safe in patients with R/R B-cell NHL. The favorable toxicity profile plus the encouraging response rates seen suggest that continued investigation of the highest dose level is warranted.
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- 2018
13. High Early Death Rates, Treatment Resistance and Short Survival of Black Adolescent and Young Adults with Acute Myeloid Leukemia
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Karilyn T. Larkin, Deedra Nicolet, Benjamin J. Kelly, Krzysztof Mrózek, Stephanie LaHaye, Katherine E. Miller, Saranga Wijeratne, Gregory Wheeler, Jessica Kohlschmidt, James S. Blachly, Alice S. Mims, Christopher J. Walker, Christopher C. Oakes, Shelley Orwick, Isaiah Boateng, Jill Buss, Adrienne Heyrosa, Helee Desai, Andrew J. Carroll, William Blum, Bayard L. Powell, Jonathan E. Kolitz, Joseph O. Moore, Robert J. Mayer, Richard A. Larson, Richard M. Stone, Electra D. Paskett, John C. Byrd, Elaine R. Mardis, and Ann-Kathrin Eisfeld
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History ,Polymers and Plastics ,Business and International Management ,Industrial and Manufacturing Engineering - Published
- 2021
14. Assessment of Outcomes After Stopping Tyrosine Kinase Inhibitors Among Patients With Chronic Myeloid Leukemia: A Nonrandomized Clinical Trial
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Neil P. Shah, Arielle Baim, Ellen K. Ritchie, Mary M. Horowitz, Michael J. Mauro, Javier Pinilla-Ibarz, Vivian G. Oehler, Alexis Visotcky, Vamsi Kota, Joseph O. Moore, Jorge E. Cortes, Michael W. Deininger, Charles A. Schiffer, Kevin P. Weinfurt, James E. Thompson, Ehab Atallah, Jill Harrell, Li Lin, Kathryn E. Flynn, Richard A. Larson, Mei-Jie Zhang, Martha Wadleigh, Richard T. Silver, Jerald P. Radich, and Bret Helton
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Adult ,Cancer Research ,medicine.medical_specialty ,Fusion Proteins, bcr-abl ,03 medical and health sciences ,0302 clinical medicine ,hemic and lymphatic diseases ,Internal medicine ,Leukemia, Myelogenous, Chronic, BCR-ABL Positive ,medicine ,Humans ,030212 general & internal medicine ,Prospective Studies ,Adverse effect ,Protein Kinase Inhibitors ,business.industry ,Hazard ratio ,Imatinib ,Middle Aged ,Discontinuation ,Dasatinib ,Clinical trial ,Oncology ,Nilotinib ,030220 oncology & carcinogenesis ,Imatinib Mesylate ,Female ,business ,Bosutinib ,medicine.drug - Abstract
Tyrosine kinase inhibitors (TKIs) have been associated with improved survival of patients with chronic myeloid leukemia (CML) but are also associated with adverse effects, especially fatigue and diarrhea. Discontinuation of TKIs is safe and is associated with the successful achievement of treatment-free remission (TFR) for some patients.To evaluate molecular recurrence (MRec) and patient-reported outcomes (PROs) after TKI discontinuation for US patients with CML.The Life After Stopping TKIs (LAST) study was a prospective single-group nonrandomized clinical trial that enrolled 172 patients from 14 US academic medical centers from December 18, 2014, to December 12, 2016, with a minimum follow-up of 3 years. Participants were adults with chronic-phase CML whose disease was well controlled with imatinib, dasatinib, nilotinib, or bosutinib. Statistical analysis was performed from August 13, 2019, to March 23, 2020.Discontinuation of TKIs.Molecular recurrence, defined as loss of major molecular response (BCR-ABL1 International Scale ratio0.1%) by central laboratory testing, and PROs (Patient-Reported Outcomes Measurement Information System computerized adaptive tests) were monitored. Droplet digital polymerase chain reaction (ddPCR) was performed on samples with undetectable BCR-ABL1 by standard real-time quantitative polymerase chain reaction (RQ-PCR).Of 172 patients, 89 were women (51.7%), and the median age was 60 years (range, 21-86 years). Of 171 patients evaluable for molecular analysis, 112 (65.5%) stayed in major molecular response, and 104 (60.8%) achieved TFR. Undetectable BCR-ABL1 by either ddPCR or RQ-PCR at the time of TKI discontinuation (hazard ratio, 3.60; 95% CI, 1.99-6.50; P .001) and at 3 months (hazard ratio, 5.86; 95% CI, 3.07-11.1; P .001) was independently associated with MRec. Molecular recurrence for patients with detectable BCR-ABL1 by RQ-PCR was 50.0% (14 of 28), undetectable BCR-ABL1 by RQ-PCR but detectable by ddPCR was 64.3% (36 of 56), and undetectable BCR-ABL1 by both ddPCR and RQ-PCR was 10.3% (9 of 87) (P ≤ .001). Of the 112 patients in TFR at 12 months, 90 (80.4%) had a clinically meaningful improvement in fatigue, 39 (34.8%) had a clinically meaningful improvement in depression, 98 (87.5%) had a clinically meaningful improvement in diarrhea, 24 (21.4%) had a clinically meaningful improvement in sleep disturbance, and 5 (4.5%) had a clinically meaningful improvement in pain interference. Restarting a TKI resulted in worsening of PROs.In this study, TKI discontinuation was safe, and 60.8% of patients remained in TFR. Discontinuation of TKIs was associated with improvements in PROs. These findings should assist patients and physicians in their decision-making regarding discontinuation of TKIs. Detectable BCR-ABL1 by RQ-PCR or ddPCR at the time of TKI discontinuation was associated with higher risk of MRec; clinical application of this finding should be confirmed in other studies.ClinicalTrials.gov Identifier: NCT02269267.
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- 2020
15. Chronic Myeloid Leukemia, Version 1.2019, NCCN Clinical Practice Guidelines in Oncology
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Peter T. Curtin, Camille N. Abboud, Kendra Sweet, Michael W. Deininger, Jerald P. Radich, Philip A. Pancari, B. Douglas Smith, David S. Snyder, Jason Gotlib, Madan Jagasia, James R. Thompson, Ellin Berman, Jessica K. Altman, Moshe Talpaz, Bhavana Bhatnagar, Michal G. Rose, Mrinal M. Patnaik, Arnel Pallera, Enkhtsetseg Purev, Hagop M. Kantarjian, Kristina M. Gregory, Joseph O. Moore, Lori J. Maness, Daniel J. DeAngelo, Ravi Bhatia, Leland Metheny, Neil P. Shah, Hema Sundar, Gabriela S. Hobbs, and David T. Yang
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0301 basic medicine ,Oncology ,medicine.medical_specialty ,medicine.drug_class ,Fusion Proteins, bcr-abl ,Chromosomal translocation ,Medical Oncology ,Real-Time Polymerase Chain Reaction ,Philadelphia chromosome ,Risk Assessment ,Tyrosine-kinase inhibitor ,Fusion gene ,03 medical and health sciences ,Myelogenous ,0302 clinical medicine ,Bone Marrow ,Leukemia, Myelogenous, Chronic, BCR-ABL Positive ,hemic and lymphatic diseases ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,Biomarkers, Tumor ,medicine ,Humans ,Philadelphia Chromosome ,Progression-free survival ,Protein Kinase Inhibitors ,Societies, Medical ,Clinical Trials as Topic ,Dose-Response Relationship, Drug ,business.industry ,Patient Selection ,Myeloid leukemia ,Prognosis ,medicine.disease ,Progression-Free Survival ,United States ,Leukemia ,030104 developmental biology ,Drug Resistance, Neoplasm ,030220 oncology & carcinogenesis ,Disease Progression ,business - Abstract
Chronic myeloid leukemia (CML) is defined by the presence of Philadelphia chromosome (Ph), resulting from a reciprocal translocation between chromosomes 9 and 22 [t(9;22] that gives rise to a BCR-ABL1 fusion gene. CML occurs in 3 different phases (chronic, accelerated, and blast phase) and is usually diagnosed in the chronic phase. Tyrosine kinase inhibitor (TKI) therapy is a highly effective first-line treatment option for all patients with newly diagnosed chronic phase CML (CP-CML). The selection TKI therapy should be based on the risk score, toxicity profile of TKI, patient's age, ability to tolerate therapy, and the presence of comorbid conditions. This manuscript discusses the recommendations outlined in the NCCN Guidelines for the diagnosis and management of patients with CP-CML.
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- 2018
16. Ten-year outcome of patients with acute myeloid leukemia not treated with allogeneic transplantation in first complete remission
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Deedra Nicolet, John C. Byrd, Sumithira Vasu, Klaus H. Metzeler, Joseph O. Moore, Krzysztof Mrózek, Heiko Becker, Jessica Kohlschmidt, Dimitrios Papaioannou, Andrew J. Carroll, Clara D. Bloomfield, Gail J. Roboz, Lisa J. Sterling, Maria R. Baer, Bayard L. Powell, Ann-Kathrin Eisfeld, Jonathan E. Kolitz, and Richard Stone
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Adult ,Male ,0301 basic medicine ,medicine.medical_specialty ,Myeloid ,Allogeneic transplantation ,Adolescent ,medicine.medical_treatment ,Abnormal Karyotype ,Hematopoietic stem cell transplantation ,Disease-Free Survival ,03 medical and health sciences ,0302 clinical medicine ,hemic and lymphatic diseases ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Humans ,Survival rate ,Retrospective Studies ,Myeloid Neoplasia ,business.industry ,Age Factors ,Hematopoietic Stem Cell Transplantation ,Myeloid leukemia ,Cancer ,Retrospective cohort study ,Hematology ,Middle Aged ,Allografts ,medicine.disease ,Survival Rate ,Leukemia, Myeloid, Acute ,Leukemia ,030104 developmental biology ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Female ,business ,Follow-Up Studies - Abstract
The probability that adult patients with de novo acute myeloid leukemia (AML) receiving intensive chemotherapy in the absence of allogeneic hematopoietic stem cell transplantation (Allo-HCT) in first complete remission (CR1) will be disease-free at 10 years after diagnosis, a long-term surrogate of cure, is unknown. To address this question, we examined 2551 AML patients (1607 aged
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- 2018
17. NCCN Guidelines Insights: Hodgkin Lymphoma, Version 1.2018
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Robert T. Chen, Andres Forero, Kami J. Maddocks, Philippe Armand, Ndiya Ogba, David S. Morgan, Francisco J. Hernandez-Ilizaliturri, Jane N. Winter, Joachim Yahalom, Carolyn Mulroney, Bouthaina S. Dabaja, Patrick B. Johnston, Joseph O. Moore, Jiayi Huang, Weiyun Z. Ai, Robert M. Dean, Rachel Rabinovitch, Craig H. Moskowitz, Jennifer L. Burns, Celeste M. Bello, Randa Tao, Cecil M. Benitez, Philip J. Bierman, Mark S. Kaminski, Vaishalee P. Kenkre, Leo I. Gordon, David G. Maloney, Monika L. Metzger, Nadia Khan, Stuart Seropian, Richard T. Hoppe, Ephraim P. Hochberg, Richard F. Ambinder, Ranjana H. Advani, and Patricia Aoun
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medicine.medical_specialty ,Adult patients ,business.industry ,MEDLINE ,Hodgkin Disease ,Clinical Practice ,03 medical and health sciences ,0302 clinical medicine ,Oncology ,030220 oncology & carcinogenesis ,Humans ,Medicine ,Hodgkin lymphoma ,business ,Intensive care medicine ,030215 immunology - Abstract
The NCCN Clinical Practice Guidelines in Oncology for Hodgkin Lymphoma (HL) provide recommendations for the management of adult patients with HL. The NCCN Guidelines Panel meets at least annually to review comments from reviewers within the NCCN Member Institutions, examine relevant data, and reevaluate and update the recommendations. These NCCN Guidelines Insights summarize recent updates centered on treatment considerations for relapsed/refractory classic HL.
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- 2018
18. Dose‐intense chemoimmunotherapy plus radioimmunotherapy in high‐risk diffuse large B‐cell lymphoma and mantle cell lymphoma: a phase <scp>II</scp> study
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Zachary Powell, David A. Rizzieri, Louis F. Diehl, Kathryn Elizabeth Hudson, Thomas W. LeBlanc, Joseph O. Moore, Anne W. Beaven, Samantha M. Thomas, and Carlos M. DeCastro
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Chemoimmunotherapy ,business.industry ,Radioimmunotherapy ,medicine.medical_treatment ,medicine ,Cancer research ,Phases of clinical research ,Mantle cell lymphoma ,Hematology ,medicine.disease ,business ,Diffuse large B-cell lymphoma ,Article - Published
- 2018
19. High Early Death Rates, Treatment Resistance and Short Survival of Black Adolescent and Young Adults (AYAs) with Acute Myeloid Leukemia (AML) (Alliance)
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Karilyn Larkin, Deedra Nicolet, Ben Kelly, Krzysztof Mrózek, Katherine E Miller, Saranga Wijeratne, Stephanie LaHaye, Jessica Kohlschmidt, James S. Blachly, Alice S. Mims, Christopher J. Walker, Christopher C. Oakes, Shelley Orwick, Isaiah Boateng, Jill Buss, Adrienne Heyrosa, Andrew J Carroll, William Blum, Bayard L. Powell, Jonathan E Kolitz, Joseph O. Moore, Robert James Mayer, Richard A. Larson, Richard M. Stone, Electra D. Paskett, John C. Byrd, Elaine R. Mardis, and Ann-Kathrin Eisfeld
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Immunology ,Cell Biology ,Hematology ,Biochemistry - Abstract
Background: AML is a highly aggressive hematologic malignancy. Patient (pt) outcomes are affected by disease-related factors including cytogenetic findings and gene mutations, as well as pt-related factors, such as age and race. Younger pts have superior survival: ~50% of pts diagnosed as AYAs (18-39 years) may be cured of their disease. However, the impact of race on the outcome and associated disease profiles in this pt population are unknown. Methods: We compared survival and molecular profiles of 655 Non-Hispanic Black and Non-Hispanic White (hereafter referred to as Black, n=89 and White, n=566) AYA AML pts treated on frontline Cancer and Leukemia Group B/Alliance for Clinical Trials in Oncology protocols based on standard intensity cytarabine/anthracycline induction therapy between 1986 and 2016. Three hundred ten pts were analyzed molecularly via targeted sequencing of 81 genes. Additionally, we performed integrated genomic profiling (whole-exome sequencing and transcriptome sequencing) and measured residual disease (MRD) in serial samples of 4 Black pts who relapsed with their disease. Results: A comparison of clinical characteristics of AYA AML pts by race revealed almost identical age and sex distribution, and we found no significant differences between clinical features at diagnosis. With regard to genetic profiles, 42% of White pts were cytogenetically normal, whereas only 18% of Black pts had cytogenetically normal AML (CN-AML; p Black AYA AML pts had worse outcomes including a higher early death rate (ED, defined as death within 30 days of diagnosis; 11% v 2%, p To gain insights into the genetic features of Black AYA AML pts at different stages of the disease, we performed integrated genomic profiling on paired leukemic samples from diagnosis and relapse of 4 Black AYA pts. In all pts, the original dominant leukemic clone persisted and was dominant at relapse (Fig. 3). This suggests that the leukemic clone persists during treatment with conventional cytotoxic chemotherapy. This observation was further supported by MRD detection of NPM1 mutations in NPM1-mutated pts at time of morphologic CR. Conclusion: Black AYA AML pts present with distinct molecular features, including very high frequencies of CBF AML, and low frequency of NPM1. Pts aged 18-29y account for the race-associated survival disparity, especially non-CBF pts who have dramatically poor survival. On the one hand, the lower CR rates combined with persistence of dominant clones at relapse suggest reduced response to induction chemotherapy, and suggests the need for different treatment intensities and/or modalities in this pt cohort. On the other hand, high early death rates are indicative of delay in diagnosis and care, including health inequities, calling for systematic changes particularly for this population. Figure 1 Figure 1. Disclosures Blachly: KITE: Consultancy, Honoraria; INNATE: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; AstraZeneca: Consultancy, Honoraria. Mims: Leukemia and Lymphoma Society's Beat AML clinical study: Consultancy, Research Funding; Aptevo: Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Glycomemetics: Research Funding; Kartos Pharmaceuticals: Research Funding; Xencor: Research Funding; Genentech: Consultancy; Abbvie: Consultancy; BMS: Consultancy; Kura Oncology: Consultancy; Syndax Pharmaceuticals: Consultancy; BMS: Consultancy; Jazz Pharmaceuticals: Consultancy; Aptevo: Research Funding. Walker: Karyopharm Therapeutics: Current Employment, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Blum: Leukemia and Lymphoma Society: Research Funding; Syndax: Honoraria; AmerisourceBergen: Honoraria; Abbvie: Honoraria; Celyad Oncology: Research Funding; Nkarta: Research Funding; Forma Therapeutics: Research Funding; Xencor: Research Funding. Larson: Rafael Pharmaceuticals: Research Funding; Epizyme: Consultancy; Astellas: Consultancy, Research Funding; Gilead: Research Funding; CVS/Caremark: Consultancy; Takeda: Research Funding; Novartis: Research Funding; Cellectis: Research Funding. Stone: Onconova: Consultancy; Boston Pharmaceuticals: Consultancy; Innate: Consultancy; Jazz: Consultancy; Novartis: Consultancy, Research Funding; AbbVie: Consultancy; GlaxoSmithKline: Consultancy; Gemoab: Membership on an entity's Board of Directors or advisory committees; Foghorn Therapeutics: Consultancy; Janssen: Consultancy; Arog: Consultancy, Research Funding; Aprea: Consultancy; Elevate Bio: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Consultancy; BerGen Bio: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Actinium: Membership on an entity's Board of Directors or advisory committees; Syndax: Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy; Syntrix/ACI: Membership on an entity's Board of Directors or advisory committees; Syros: Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy; Agios: Consultancy, Research Funding; Macrogenics: Consultancy. Paskett: Pfizer: Research Funding; Merck: Research Funding. Byrd: Vincerx Pharmaceuticals: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Newave: Membership on an entity's Board of Directors or advisory committees; Novartis, Trillium, Astellas, AstraZeneca, Pharmacyclics, Syndax: Consultancy, Honoraria. Eisfeld: Karyopharm (spouse): Current Employment.
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- 2021
20. Multi-Dimensional Analysis of Adult Acute Myeloid Leukemia (AML) Landscape Cross-Continents Reveals Age Associated Trends in Mutations and Outcomes
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Wolfgang Hiddemann, Christopher C. Oakes, Dennis Görlich, Aarif M. N. Batcha, Alice S. Mims, Shelley Orwick, Stephanie Schneider, Maria Cristina Sauerland, Christopher J. Walker, Karilyn Larkin, Richard Stone, Vindi Jurinovic, Maja Rothenberg-Thurley, Klaus H. Metzeler, Joseph O. Moore, William Blum, James S. Blachly, Andrew J. Carroll, Karsten Spiekermann, Bernhard J. Woermann, Utz Krug, John C. Byrd, Jessica Kohlschmidt, Jan Braess, Richard A. Larson, Deedra Nicolet, Robert J. Mayer, Wolfgang E. Berdel, Bayard L. Powell, Jonathan E. Kolitz, Ann-Kathrin Eisfeld, Monica Cusan, Krzysztof Mrózek, and Tobias Herold
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Oncology ,medicine.medical_specialty ,Internal medicine ,Immunology ,medicine ,Adult Acute Myeloid Leukemia ,Cell Biology ,Hematology ,Biology ,Multi dimensional analysis ,Biochemistry - Abstract
Background: AML is a disease affecting predominantly older patients (pts), but does occur across the entire age spectrum; younger adults [age Methods: We analyzed the molecular profiles of 2,823 adult AML pts enrolled onto clinical frontline protocols of 2 large cooperative study groups from 2 continents [US, Cancer and Leukemia Group B (CALGB)/Alliance for Clinical Trials in Oncology (Alliance), n=1743; Germany, AML Cooperative Group [AMLCG], n=1080] between 1986 and 2016. Treatment of all pts included intensive induction therapy, whereas pts enrolled on CALGB/Alliance protocols precluded allogeneic transplantation in 1 st complete remission. Pts in both cohorts were profiled for molecular features via targeted sequencing platforms. Frequencies of mutations genes and selected cytogenetic findings were then calculated in both datasets for the group of pts aged 18-24 y and for older pts by 5-year intervals until the age of 74 y and for pts older than 75 y. We also analyzed survival outcomes of 1,669 AML pts younger than 60 y using the same age intervals up to age 59 y. Results: Our side-by-side analysis shows remarkable congruence of results between German and US pt populations. Selected AML-associated gene mutations (mutation frequency ≥4%) and recurrent cytogenetic abnormalities followed 3 basic distribution patterns across the age spectrum (Fig. 1A): group 1 with increasing frequency with increasing age [ASXL1, BCOR, IDH1/2, RUNX1, SRSF2, TET2, TP53; complex karyotype and cytogenetically normal AML (CN-AML)]; group 2 with decreasing frequency with increasing age (CEBPA, EZH2, FLT3-TKD, GATA2, KIT, KRAS, PTPN11, NRAS, WT1; inv(16), t(8;21) and 11q23/KMT2A rearrangements) and group 3 with non-linear frequency distribution, which included the 3 most common AML-associated gene mutations (NPM1, DNMT3A, FLT3-ITD), SF3B1 and mutations in the cohesin complex genes (RAD21, SMC1A, SMC3, STAG2) (Fig. 1A). Notably, within the first 2 distribution groups, there seem to be no obvious age that could serve as a cut point separating age groups that are markedly different with regard to their molecular patterns. Particularly, this includes an age group that is commonly used for pt cohort definitions such as pts aged 18-39 y referred to as adolescent and young adults (AYA) or even treatment decisions and eligibility (eg, ages 60 or 65 and older for consideration as elderly AML). With respect to pt outcomes, expectedly, there was almost linear shortening of overall survival (OS) as age increased (p Conclusions: To our knowledge, this is the first large scale depiction of mutational patterns in AML inclusive of the entire adult age spectrum. Our international study demonstrates that patterns of individual mutations based on age are remarkably consistent between countries, and defy assortment based on typical age conventions. Given the continuous distribution of either increasing or decreasing frequency of many mutations, there are distinctly different mutational profiles for the youngest pts compared with older pts, however choosing a precise cut-off, such as age 39 for AYA pts or 59 for consideration as "younger AML", does not seem to be supported by our analyses. This observation supports a more personalized approach that also considers molecular subgroups in clinical practice instead of the age rigidity set in many clinical trials. *shared first: M.C.,K.L.; #last: T.H.,AK.E. Figure 1 Figure 1. Disclosures Berdel: Philogen S.p.A.: Consultancy, Current equity holder in publicly-traded company, Honoraria, Membership on an entity's Board of Directors or advisory committees. Hiddemann: F. Hoffmann-La Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Research Funding. Blachly: KITE: Consultancy, Honoraria; INNATE: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; AstraZeneca: Consultancy, Honoraria. Mims: Glycomemetics: Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Aptevo: Research Funding; Leukemia and Lymphoma Society's Beat AML clinical study: Consultancy, Research Funding; Xencor: Research Funding; Kartos Pharmaceuticals: Research Funding; Genentech: Consultancy; Abbvie: Consultancy; BMS: Consultancy; Kura Oncology: Consultancy; Syndax Pharmaceuticals: Consultancy; BMS: Consultancy; Jazz Pharmaceuticals: Consultancy; Aptevo: Research Funding. Walker: Karyopharm Therapeutics: Current Employment, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Blum: Celyad Oncology: Research Funding; Forma Therapeutics: Research Funding; Xencor: Research Funding; Nkarta: Research Funding; Leukemia and Lymphoma Society: Research Funding; Abbvie: Honoraria; AmerisourceBergen: Honoraria; Syndax: Honoraria. Larson: Epizyme: Consultancy; Astellas: Consultancy, Research Funding; Gilead: Research Funding; CVS/Caremark: Consultancy; Takeda: Research Funding; Novartis: Research Funding; Rafael Pharmaceuticals: Research Funding; Cellectis: Research Funding. Stone: Syntrix/ACI: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Research Funding; Astellas: Membership on an entity's Board of Directors or advisory committees; BerGen Bio: Membership on an entity's Board of Directors or advisory committees; Actinium: Membership on an entity's Board of Directors or advisory committees; Elevate Bio: Membership on an entity's Board of Directors or advisory committees; Syndax: Membership on an entity's Board of Directors or advisory committees; Onconova: Consultancy; Jazz: Consultancy; Janssen: Consultancy; Innate: Consultancy; GlaxoSmithKline: Consultancy; Gemoab: Membership on an entity's Board of Directors or advisory committees; Foghorn Therapeutics: Consultancy; Boston Pharmaceuticals: Consultancy; Bristol Myers Squibb: Consultancy; AbbVie: Consultancy; Arog: Consultancy, Research Funding; Aprea: Consultancy; Amgen: Membership on an entity's Board of Directors or advisory committees; Syros: Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy; Agios: Consultancy, Research Funding; Celgene: Consultancy; Macrogenics: Consultancy. Byrd: Vincerx Pharmaceuticals: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Novartis, Trillium, Astellas, AstraZeneca, Pharmacyclics, Syndax: Consultancy, Honoraria; Newave: Membership on an entity's Board of Directors or advisory committees. Metzeler: Jazz Pharmaceuticals: Consultancy; Novartis: Consultancy; Daiichi Sankyo: Honoraria; Astellas: Honoraria; AbbVie: Honoraria; Pfizer: Consultancy; Celgene/BMS: Consultancy, Honoraria, Research Funding. Eisfeld: Karyopharm (spouse): Current Employment.
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- 2021
21. Acute Myeloid Leukemia, Version 3.2017, NCCN Clinical Practice Guidelines in Oncology
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Frederick R. Appelbaum, Keith W. Pratz, Steven Coutre, Dale L. Bixby, Michael Gary Martin, Steven D. Gore, Melanie Fiorella, William Blum, Richard Stone, Deniz Peker, Martin S. Tallman, Daniel A. Pollyea, Farhad Ravandi, Camille N. Abboud, Vijaya Raj Bhatt, Jeffrey E. Lancet, Rebecca L. Olin, Matthew J. Wieduwilt, Stephen A. Strickland, Lori J. Maness, Daniel A. Arber, James M. Foran, Aric C. Hall, Guido Marcucci, Patricia Kropf, Eunice S. Wang, Paul J. Shami, Amir T. Fathi, Kristina M. Gregory, Ndiya Ogba, Jessica K. Altman, Marcos de Lima, Joseph O. Moore, and Margaret R. O'Donnell
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0301 basic medicine ,Oncology ,medicine.medical_specialty ,Myeloid ,MEDLINE ,03 medical and health sciences ,0302 clinical medicine ,hemic and lymphatic diseases ,Internal medicine ,medicine ,Humans ,Disease management (health) ,neoplasms ,Acute leukemia ,business.industry ,Age Factors ,Disease Management ,Myeloid leukemia ,medicine.disease ,Clinical Practice ,Transplantation ,Leukemia, Myeloid, Acute ,Leukemia ,030104 developmental biology ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,business - Abstract
Acute myeloid leukemia (AML) is the most common form of acute leukemia among adults and accounts for the largest number of annual deaths due to leukemias in the United States. Recent advances have resulted in an expansion of treatment options for AML, especially concerning targeted therapies and low-intensity regimens. This portion of the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for AML focuses on the management of AML and provides recommendations on the workup, diagnostic evaluation and treatment options for younger (age
- Published
- 2017
22. Hodgkin Lymphoma Version 1.2017, NCCN Clinical Practice Guidelines in Oncology
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Peter Mauch, Rachel Rabinovitch, Ephraim P. Hochberg, David G. Maloney, Karl Bernat, Matthew M. Poppe, Stuart Seropian, Cecil M. Benitez, Richard T. Hoppe, Robert T. Chen, Weiyun Z. Ai, Andres Forero, Nadia Khan, Patricia Aoun, Bouthaina S. Dabaja, Monika L. Metzger, Patrick B. Johnston, David S. Morgan, Joseph O. Moore, Jane N. Winter, Mitchell R. Smith, Carolyn Mulroney, Ndiya Ogba, Joachim Yahalom, Francisco J. Hernandez-Ilizaliturri, Hema Sundar, Jiayi Huang, Kristie A. Blum, Ranjana H. Advani, Leo I. Gordon, Celeste M. Bello, Mark S. Kaminski, Vaishalee P. Kenkre, Philip J. Bierman, Craig H. Moskowitz, Jennifer L. Burns, and Richard F. Ambinder
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Oncology ,Treatment response ,medicine.medical_specialty ,Chemotherapy ,business.industry ,medicine.medical_treatment ,Medical Oncology ,Prognosis ,Hodgkin Disease ,United States ,03 medical and health sciences ,0302 clinical medicine ,Current management ,030220 oncology & carcinogenesis ,Internal medicine ,medicine ,Humans ,Hodgkin lymphoma ,Initial treatment ,Combined Modality Therapy ,Neoplasm staging ,business ,Neoplasm Staging ,030215 immunology - Abstract
This portion of the NCCN Guidelines for Hodgkin lymphoma (HL) focuses on the management of classical HL. Current management of classical HL involves initial treatment with chemotherapy or combined modality therapy followed by restaging with PET/CT to assess treatment response using the Deauville criteria (5-point scale). The introduction of less toxic and more effective regimens has significantly advanced HL cure rates. However, long-term follow-up after completion of treatment is essential to determine potential long-term effects.
- Published
- 2017
23. Clinical outcomes in chronic lymphocytic leukaemia associated with expression of CD5, a negative regulator of B-cell receptor signalling
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Daphne R. Friedman, Alicia D. Volkheimer, J. Brice Weinberg, Eross Guadalupe, and Joseph O. Moore
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Adult ,Male ,Cell ,B-cell receptor ,Receptors, Antigen, B-Cell ,chemical and pharmacologic phenomena ,CD5 Antigens ,Article ,03 medical and health sciences ,Therapeutic approach ,0302 clinical medicine ,immune system diseases ,hemic and lymphatic diseases ,Biomarkers, Tumor ,Medicine ,Humans ,Receptor ,Aged ,Aged, 80 and over ,B-Lymphocytes ,business.industry ,breakpoint cluster region ,Virginia ,hemic and immune systems ,Hematology ,Middle Aged ,Prognosis ,Leukemia, Lymphocytic, Chronic, B-Cell ,medicine.anatomical_structure ,Signalling ,030220 oncology & carcinogenesis ,Cohort ,Cancer research ,Female ,CD5 ,business ,030215 immunology ,Signal Transduction - Abstract
Chronic lymphocytic leukaemia (CLL) is characterized by expression of CD5 on clonal B cells, and is partly driven by activated B-cell receptor (BCR) signalling. While CD5 is known to be a negative regulator of BCR signalling, it is unknown if variability in CD5 expression exists among patients and whether CLL cell CD5 expression affects CLL clinical outcomes. We assessed the extent to which CD5 expression is correlated with clinical outcomes, and whether this information adds to currently used prognostic markers. We evaluated CD5 expression from 1275 blood samples, established prognostic markers and time to event data from 423 CLL patients followed at the Duke University and Durham VA Medical Centers. CD5 median fluorescence intensity (MFI) was largely stable over time in ssindividual patients, but ranged between 0.5 and 760 in the entire cohort. Lower CD5 MFI was significantly associated with a shorter time to first therapy. CD5 MFI, combined with established clinical and molecular prognostic markers, significantly improved risk-stratification. CD5 may affect disease outcomes by suppressing signalling through the BCR. Thus, a strategy to modulate CLL cell CD5 expression or function could be a therapeutic approach in CLL.
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- 2018
24. Patient-Reported Outcome Results from the U.S. Life after Stopping TKIs (LAST) Study in Patients with Chronic Myeloid Leukemia
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Ehab Atallah, Michael W. Deininger, Kevin P. Weinfurt, James E. Thompson, Martha Wadleigh, Vivian G. Oehler, Javier Pinilla Ibarz, Neil P. Shah, Li Lin, Charles A. Schiffer, Kathryn E. Flynn, Richard A. Larson, Jerald P. Radich, Ellen K. Ritchie, Vamsi Kota, Joseph O. Moore, Jorge E. Cortes, Richard T. Silver, and Michael J. Mauro
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Oncology ,medicine.medical_specialty ,business.industry ,Immunology ,Myeloid leukemia ,Cell Biology ,Hematology ,Biochemistry ,Dasatinib ,Imatinib mesylate ,Nilotinib ,Internal medicine ,medicine ,In patient ,Patient-reported outcome ,business ,Bcr-Abl Tyrosine Kinase ,Bosutinib ,medicine.drug - Abstract
Background: Treatment of chronic myeloid leukemia (CML) with a tyrosine kinase inhibitor (TKI) offers significant improvements over previous treatments in terms of survival and toxicity yet has been associated with reduced health-related quality of life and very high cost. Discontinuing TKIs with regular monitoring is safe, but little is known about the impact of discontinuation on patient-reported outcomes (PROs). In the largest U.S. study to date, we evaluated molecular recurrence of CML and PROs after TKI discontinuation. Methods: The Life After Stopping TKIs (LAST) study was a prospective single-group longitudinal study. Key inclusion criteria were age > 18 years, patient on TKI therapy (imatinib, dasatinib, nilotinib, or bosutinib) for > 3 years with documented BCR-ABL < 0.01% by PCR for > 2 years, and no previous TKI resistance. We monitored disease outcome (PCRs by central lab) and PROs (PROMIS computerized adaptive tests via REDCap) monthly for the first 6 months, every 2 months until 24 months, then every 3 months until 36 months. Molecular recurrence was defined as > 0.1% BCR-ABL IS by central lab (loss of major molecular response [MMR]). We considered 3 points to be clinically meaningful and hypothesized that by 6 months after TKI discontinuation, fatigue, depression, sleep disturbance, and diarrhea would improve by at least 3 points each, corresponding to a standardized effect size of 0.3. Given reports of a withdrawal syndrome of musculoskeletal pain in some patients after discontinuation, pain was an additional outcome of particular interest. For each PRO domain, we estimated a polynomial piecewise linear mixed effects model that specified one nonlinear trajectory after TKI discontinuation and, for those with molecular recurrence, another trajectory after TKI restart. The models included patient-level random effects for the intercepts and linear slopes. Results: From 12/2014 to 12/2016, 172 patients enrolled from 14 U.S. sites. Median age was 60 years (range 21-86) and 89 (52%) were female. The median time on TKI prior to enrollment was 81 months (IQR 54-123). With a minimum follow-up of 24 months, 107 (62%) patients remained in a treatment free remission (TFR). Reasons for restarting therapy were: loss of MMR by central (n=56) or local (n=2) lab, patient decision (n=4), and withdrawal syndrome (n=3). Missing PRO data was minimal (< 5%) with > 2000 assessments completed. For patients in TFR at 6 months, the average estimated improvement in fatigue was 2.6 points (95% CI 2.5-2.7), depression was 1.9 points (95% CI 1.8-1.9), sleep disturbance was 0.9 points (95% CI 0.8-1.0), and diarrhea was 2.7 points (95% CI 2.6-2.7). The average estimated worsening in pain interference (i.e., the extent to which pain affects daily life) was 0.4 points (95% CI 0.3-0.5). The figure shows the distribution of estimated change for each domain at 6 months. All patients showed improvements in depression, diarrhea, and fatigue. About 1 in 6 patients (17%) experienced a clinically meaningful (i.e., at least 3 points) improvement in fatigue and/or diarrhea at 6 months. Conclusion: The LAST study is the largest US TKI discontinuation study to date, and the first to include comprehensive PRO measurement. For patients in TFR at 6 months, TKI discontinuation conferred modest benefits in fatigue and diarrhea on average, with a negligible increase in pain interference. Some patients experienced more notable improvements in fatigue and diarrhea. Planned secondary analyses will include change over time up to 3 years and evaluation of additional PRO domains, including anxiety, physical function, social function, and sexual function. Our results provide important new evidence to support shared patient-provider clinical decision making regarding TKI discontinuation for patients with CML. Figure. Disclosures Radich: Novartis: Other: RNA Sequencing; TwinStrand Biosciences: Research Funding. Mauro:Pfizer: Consultancy; Takeda: Consultancy; Novartis Oncology: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy. Pinilla Ibarz:Sanofi: Speakers Bureau; Abbvie: Consultancy, Speakers Bureau; Teva: Consultancy; Janssen: Consultancy, Speakers Bureau; Novartis: Consultancy; Takeda: Consultancy, Speakers Bureau; Bayer: Speakers Bureau; TG Therapeutics: Consultancy; Bristol-Myers Squibb: Consultancy. Larson:Celgene: Consultancy; Novartis: Honoraria, Other: Contracts for clinical trials; Agios: Consultancy. Oehler:Blueprint Medicines: Consultancy; NCCN: Consultancy; Pfizer Inc.: Research Funding. Deininger:Humana: Honoraria; Incyte: Honoraria; Blueprint: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Honoraria, Research Funding; Ascentage Pharma: Consultancy, Honoraria; TRM: Consultancy; Sangoma: Consultancy; Fusion Pharma: Consultancy; Adelphi: Consultancy; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria; Sangamo: Consultancy. Shah:Bristol-Myers Squibb: Research Funding. Ritchie:Tolero: Other: Advisory board; Celgene: Other: Advisory board; Celgene, Novartis: Other: travel support; Jazz Pharmaceuticals: Research Funding; Celgene, Incyte, Novartis, Pfizer: Consultancy; AStella, Bristol-Myers Squibb, Novartis, NS Pharma, Pfizer: Research Funding; Ariad, Celgene, Incyte, Novartis: Speakers Bureau; Genentech: Other: Advisory board; Pfizer: Other: Advisory board, travel support; agios: Other: Advisory board. Silver:PharmEssentia: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Cortes:Sun Pharma: Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Forma Therapeutics: Consultancy, Honoraria, Research Funding; BiolineRx: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Daiichi Sankyo: Consultancy, Honoraria, Research Funding; Jazz Pharmaceuticals: Consultancy, Research Funding; Biopath Holdings: Consultancy, Honoraria; Immunogen: Consultancy, Honoraria, Research Funding; Merus: Consultancy, Honoraria, Research Funding; Astellas Pharma: Consultancy, Honoraria, Research Funding. Atallah:Jazz: Consultancy; Helsinn: Consultancy; Pfizer: Consultancy; Takeda: Consultancy, Research Funding; Jazz: Consultancy; Helsinn: Consultancy; Novartis: Consultancy.
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- 2019
25. Design and rationale for the life after stopping tyrosine kinase inhibitors (LAST) study, a prospective, single-group longitudinal study in patients with chronic myeloid leukemia
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Kathryn E. Flynn, Richard A. Larson, Li Lin, Martha Wadleigh, Mary M. Horowitz, Richard T. Silver, Ehab Atallah, Michael J. Mauro, Mei-Jie Zhang, Jessica Guhl, Joseph O. Moore, Charles A. Schiffer, Javier Pinilla-Ibarz, Michael W. Deininger, Jorge E. Cortes, Neil P. Shah, Vivian G. Oehler, Jerald P. Radich, Kevin P. Weinfurt, James E. Thompson, and Ellen K. Ritchie
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Oncology ,Cancer Research ,bcr-abl ,Fusion Proteins, bcr-abl ,Tyrosine kinase inhibitor ,Tyrosine-kinase inhibitor ,Targeted therapy ,Study Protocol ,0302 clinical medicine ,Clinical Protocols ,Recurrence ,Longitudinal Studies ,Molecular Targeted Therapy ,Chronic ,Patient-reported outcome ,Cancer ,Leukemia ,Chronic myeloid leukemia ,Myeloid leukemia ,Hematology ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,3. Good health ,Dasatinib ,Clinical trial ,Research Design ,030220 oncology & carcinogenesis ,6.1 Pharmaceuticals ,Public Health and Health Services ,Bosutinib ,medicine.drug ,medicine.medical_specialty ,medicine.drug_class ,Clinical Trials and Supportive Activities ,Oncology and Carcinogenesis ,Antineoplastic Agents ,Discontinuation ,lcsh:RC254-282 ,03 medical and health sciences ,Rare Diseases ,Clinical Research ,Internal medicine ,Leukemia, Myelogenous, Chronic, BCR-ABL Positive ,Genetics ,medicine ,Humans ,Patient Reported Outcome Measures ,Oncology & Carcinogenesis ,Watchful Waiting ,Protein Kinase Inhibitors ,business.industry ,Evaluation of treatments and therapeutic interventions ,Fusion Proteins ,Imatinib ,Study design ,respiratory tract diseases ,Good Health and Well Being ,Nilotinib ,Quality of Life ,BCR-ABL Positive ,business ,030215 immunology ,Myelogenous - Abstract
Treatment of chronic myeloid leukemia with a tyrosine kinase inhibitor (TKI) offers significant improvements over previous treatments in terms of survival and toxicity yet nevertheless is associated with reduced health-related quality of life and very high cost. Several small studies from Europe and Australia suggested that discontinuing TKIs with regular monitoring was safe. The Life After Stopping TKIs (LAST) study is a large, U.S.-based study that aims to improve the evidence for clinical decision making regarding TKI discontinuation with monitoring in patients with chronic myeloid leukemia who have a deep molecular response to TKI therapy. The LAST study is a non-randomized, prospective, single-group longitudinal study of 173 patients. The co-primary objectives are to determine the proportion of patients who develop molecular recurrence (> 0.1% BCR-ABLIS) after discontinuing one of four TKIs (imatinib, dasatinib, nilotinib, or bosutinib) and to compare the patient-reported health status of patients before and after stopping TKIs. Outcomes are assessed at baseline and throughout the 36-month study follow-up period with a central laboratory used for blood samples. All samples with undetectable BCR-ABL are also examined using digital polymerase chain reaction, which is a more sensitive nanofluidic polymerase chain reaction system. Because of their high cost and side effects, discontinuation of TKIs for patients with chronic myeloid leukemia who have a deep molecular response to TKI therapy is a promising approach to treatment. The LAST study is the largest U.S.-based TKI discontinuation study. It is the first to allow participation from patients on any of 4 first- and second-generation TKIs, includes a robust approach to measurement of clinical and patient-reported outcomes, and is using digital polymerase chain reaction to explore better prediction of safe discontinuation. This study was registered prospectively on October 21, 2014 and assigned trial number NCT02269267 .
- Published
- 2018
26. MP37-01 UTILIZATION AND IMPACT OF POST-CHEMOTHERAPY RETROPERITONEAL LYMPH NODE DISSECTION IN ADVANCED NON-SEMINOMATOUS GERM CELL TUMOR
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Nirmish Singla, Timothy Clinton, Aditya Bagrodia, Yull Edwin Arriaga, Yuval Freifeld, Vitaly Margulis, Ryan Hutchinson, Solomon L. Woldu, Yair Lotan, Laura-Maria Krabbe, and Joseph O. Moore
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medicine.medical_specialty ,Retroperitoneal lymph node dissection ,medicine.anatomical_structure ,business.industry ,Urology ,medicine.medical_treatment ,Medicine ,Radiology ,business ,Post-chemotherapy ,Germ cell - Published
- 2018
27. Hodgkin Lymphoma, Version 2.2015
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David G. Maloney, Stuart Seropian, Richard T. Hoppe, Bouthaina S. Dabaja, Craig H. Moskowitz, Jennifer L. Burns, Monika L. Metzger, Celeste M. Bello, Philip J. Bierman, Francisco J. Hernandez-Ilizaliturri, Matthew M. Poppe, Peter Mauch, Weiyun Z. Ai, Christina Tsien, Kristie A. Blum, Ranjana H. Advani, Robert T. Chen, Joachim Yahalom, Andres Forero, Patricia Aoun, David S. Morgan, Richard F. Ambinder, Patrick B. Johnston, Joseph O. Moore, Hema Sundar, Jane N. Winter, Carolyn Mulroney, Jiayi Huang, Cecil M. Benitez, Ephraim P. Hochberg, Rachel Rabinovitch, Nadia Khan, and Leo I. Gordon
- Subjects
Oncology ,medicine.medical_specialty ,Pathology ,Chemotherapy ,medicine.diagnostic_test ,business.industry ,medicine.medical_treatment ,Refractory Disease ,Malignancy ,medicine.disease ,Lymphatic system ,immune system diseases ,Positron emission tomography ,hemic and lymphatic diseases ,Internal medicine ,medicine ,Hodgkin lymphoma ,Combined Modality Therapy ,Brentuximab vedotin ,business ,medicine.drug - Abstract
Hodgkin lymphoma (HL) is an uncommon malignancy involving lymph nodes and the lymphatic system. Classical Hodgkin lymphoma (CHL) and nodular lymphocyte-predominant Hodgkin lymphoma are the 2 main types of HL. CHL accounts for most HL diagnosed in the Western countries. Chemotherapy or combined modality therapy, followed by restaging with PET/CT to assess treatment response using the Deauville criteria (5-point scale), is the standard initial treatment for patients with newly diagnosed CHL. Brentuximab vedotin, a CD30-directed antibody-drug conjugate, has produced encouraging results in the treatment of relapsed or refractory disease. The potential long-term effects of treatment remain an important consideration, and long-term follow-up is essential after completion of treatment.
- Published
- 2015
28. Blast Phase in Chronic Myelogenous Leukemia Is Skewed Toward Unusual Blast Types in Patients Treated With Tyrosine Kinase Inhibitors
- Author
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Anand S. Lagoo, Yang Shi, Jennifer H. Crow, Andrew J. Rand, and Joseph O. Moore
- Subjects
medicine.medical_specialty ,Pathology ,Myeloid ,medicine.drug_class ,business.industry ,Cytogenetics ,General Medicine ,Blast Phase ,medicine.disease ,Tyrosine-kinase inhibitor ,respiratory tract diseases ,medicine.anatomical_structure ,Immunophenotyping ,hemic and lymphatic diseases ,medicine ,Bone marrow ,business ,Tyrosine kinase ,Chronic myelogenous leukemia - Abstract
Objectives To compare the features of the blast phase of chronic myelogenous leukemia (CML) in patients treated with tyrosine kinase inhibitors (TKIs) with those in the pre-TKI era. Methods Sixty-seven patients with blast phase CML were identified in the Duke Pathology database from 1991 to 2011. The morphology and immunophenotype of blasts were evaluated, along with cytogenetic studies and associated findings in the peripheral blood and bone marrow. Results In the TKI era, the blasts were more frequently of a type other than the usual myeloid or lymphoid types when compared with the pre-TKI era. Blast phase in TKI-treated patients was associated with a higher peripheral WBC count and a lower blast percentage in the bone marrow. Of the 23 patients with cytogenetic studies during blast phase, additional cytogenetic changes more frequently occurred in patients with an unusual blast type, and some patients showed these changes months before the onset of blast phase. Conclusions Blast phase CML in TKI- and non-TKI-treated patients differs in the morphology and immunophenotype of blasts, cytogenetic findings, and associated findings in the peripheral blood and bone marrow.
- Published
- 2015
29. SU-E-T-212: Clinical Deployment of an Automatic Planning Interface for Overlap Volume Histogram Based Treatment Planning
- Author
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Todd McNutt, Joseph O. Moore, Wuyang Yang, Joseph M. Herman, and K. Evans
- Subjects
Software deployment ,Computer science ,medicine.medical_treatment ,Histogram ,medicine ,Dosimetry ,Dosimetrist ,General Medicine ,Data mining ,computer.software_genre ,Radiation treatment planning ,computer ,Tomotherapy - Abstract
Purpose: To develop and deploy an interface to support automatic treatment planning which predicts achievable dose levels for organs at risk (OARs) from patients with similar or more complicated anatomies queried from a database. This interface will provide an easy to use method of selecting the best known achievable dose values for a given patient, and use them to automate the planning process. Methods: An overlap volume histogram (OVH) describes the distance a target structure can be expanded with the volume of the compared overlap structure. An OVH is generated for each target/critical structure pair and stored in a database with dose‐volume histograms (DVHs) for each patient. For all patients, structures are consistently named by mapping ROI names to a set of common names. For a new patient, the patient database is queried for the lowest achievable dose for each OAR from patients in the database with the same or lower overlap distance. The plan parameters and generated objectives are then automatically loaded into treatment planning system for optimization. The final clinical plan from each patient is added to the database to improve the results of future queries. Results: The system has been accepted by the dosimetrists for clinical use. Automatically generated plans required less dosimetrist interaction to achieve similar coverage to manually generated plans while OAR doses were reduced or no worse than the manually generated plans. Conclusion: Automatic planning tools can aid dosimetrists in quickly generating plans which maintain target coverage and produce comparable or reduced dose to OARs. Our interface has simplified the process enabling the broader use of the system across our dosimetry staff. Philips stock ownership Philips Sponsored Research Elekta Sponsored Research Elekta Patent License Accuray (Tomotherapy) Patent License
- Published
- 2017
30. NCCN Guidelines Insights: Chronic Myeloid Leukemia, Version 1.2017
- Author
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Kristina M. Gregory, Madan Jagasia, Hagop M. Kantarjian, Enkhtsetseg Purev, Joseph O. Moore, B. Douglas Smith, Daniel J. DeAngelo, Patricia Kropf, Michal G. Rose, Vishnu Reddy, Kendra Sweet, Raoul Tibes, Camille N. Abboud, Neil P. Shah, Hema Sundar, Evelena P. Ontiveros, Gabriela S. Hobbs, R. Tanner Hagelstrom, Arnel Pallera, Michael W. Deininger, David T. Yang, Ellin Berman, Bhavana Bhatnagar, Peter T. Curtin, David S. Snyder, Jason Gotlib, Jerald P. Radich, Albert Thomas Quiery, Jessica K. Altman, and Leland Metheny
- Subjects
0301 basic medicine ,Adult ,Pediatrics ,medicine.medical_specialty ,Myeloid ,media_common.quotation_subject ,MEDLINE ,Fertility ,Reproductive age ,03 medical and health sciences ,0302 clinical medicine ,Pregnancy ,hemic and lymphatic diseases ,Medicine ,Humans ,Child ,neoplasms ,Protein Kinase Inhibitors ,media_common ,Aged ,Evidence-Based Medicine ,business.industry ,Myeloid leukemia ,Abnormalities, Drug-Induced ,medicine.disease ,Prognosis ,Leukemia ,030104 developmental biology ,medicine.anatomical_structure ,Oncology ,Withholding Treatment ,030220 oncology & carcinogenesis ,Leukemia, Myeloid, Chronic-Phase ,Practice Guidelines as Topic ,Female ,business ,Pregnancy Complications, Neoplastic ,Pediatric population - Abstract
The NCCN Guidelines for Chronic Myeloid Leukemia (CML) provide recommendations for the management of chronic-phase and advanced-phase CML in adult patients. The median age of disease onset is 67 years. However, because CML occurs in all age groups, clinical care teams should be prepared to address issues relating to fertility and pregnancy with patients who are of reproductive age at the time of diagnosis. CML is relatively rare in children and there are no evidence-based recommendations for the management of CML in pediatric population. These NCCN Guidelines Insights discuss special considerations for the management of CML during pregnancy and for the management of CML in the pediatric population.
- Published
- 2016
31. Phase II study of dose-attenuated bortezomib, cyclophosphamide and dexamethasone ('VCD-Lite') in very old or otherwise toxicity-vulnerable adults with newly diagnosed multiple myeloma
- Author
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Carlos D. DeCastro, Emily Sellars, Zhiguo Li, Cristina G. Gasparetto, Gwynn D. Long, Joseph O. Moore, Yubin Kang, and Sascha A. Tuchman
- Subjects
Oncology ,Male ,medicine.medical_specialty ,Cyclophosphamide ,medicine.medical_treatment ,Phases of clinical research ,Kaplan-Meier Estimate ,Dexamethasone ,Bortezomib ,03 medical and health sciences ,0302 clinical medicine ,Risk Factors ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Humans ,Geriatric Assessment ,Multiple myeloma ,Lenalidomide ,Aged ,Aged, 80 and over ,Chemotherapy ,Dose-Response Relationship, Drug ,business.industry ,Induction Chemotherapy ,medicine.disease ,Surgery ,Intention to Treat Analysis ,030220 oncology & carcinogenesis ,Toxicity ,Early Termination of Clinical Trials ,Female ,Geriatrics and Gerontology ,business ,Multiple Myeloma ,030215 immunology ,medicine.drug - Abstract
Objectives Multiple myeloma (MM) primarily strikes older adults, but full-dose chemotherapy such as bortezomib (Velcade), cyclophosphamide and dexamethasone (VCD) is often excessively toxic to very old or frail adults and those with substantial comorbidities. We piloted dose-attenuated VCD ("VCD-Lite") in such vulnerable adults with newly diagnosed MM (NDMM). Materials and Methods Subjects with NDMM and a high risk of therapy-related toxicity due to factors above received bortezomib 1.3mg/m 2 subcutaneously, cyclophosphamide 300mg/m 2 and dexamethasone 40mg orally, all on days 1, 8, and 15 of a 28day cycle for eight cycles, followed by indefinite, alternating bortezomib and lenalidomide maintenance. Toxicity, overall response rate (ORR), progression-free and overall survival (PFS and OS) were determined. The Cancer and Aging Research Group geriatric assessment (CARG GA) was administered at baseline in an exploratory manner as a predictor of severe toxicity. Results 14 patients went on the study, which was closed early due to slow accrual. Intention-to-treat ORR was 64%. 64% of patients experienced grade ≥3 adverse events, the majority of which were unlikely therapy-related. Median PFS was 24.2months and OS 29.7months, with 14%, 36% and 29% of patients discontinuing study drugs due to toxicity, MM progression and other reasons respectively. Baseline CARG GA was successfully completed by all subjects but one. Conclusion VCD-Lite is a viable option for vulnerable adults with NDMM. CARG GA is feasible. Further studies to optimize therapy and to explore CARG GA as a toxicity predictor are vital.
- Published
- 2016
32. Chronic Myelogenous Leukemia, Version 1.2014
- Author
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Madan Jagasia, Kristina M. Gregory, Arnel Pallera, David S. Snyder, Jerald P. Radich, Jason Gotlib, Javier Pinilla-Ibarz, Ellin Berman, Susan O'Brien, Daniel J. DeAngelo, Jessica K. Altman, Patricia Kropf, Neil P. Shah, Steven M. Devine, Hema Sundar, B. Douglas Smith, Joseph O. Moore, Mojtaba Akhtari, Vishnu Reddy, Meir Wetzler, Amir T. Fathi, Michael W. Deininger, and Camille N. Abboud
- Subjects
Oncology ,medicine.medical_specialty ,medicine.drug_class ,International scale ,Fusion Proteins, bcr-abl ,Antineoplastic Agents ,Article ,Tyrosine-kinase inhibitor ,Myelogenous ,Leukemia, Myelogenous, Chronic, BCR-ABL Positive ,hemic and lymphatic diseases ,Internal medicine ,medicine ,Humans ,Protein Kinase Inhibitors ,business.industry ,Imatinib ,Prognosis ,medicine.disease ,Surgery ,Dasatinib ,Leukemia ,Nilotinib ,business ,Chronic myelogenous leukemia ,medicine.drug - Abstract
The 2014 NCCN Clinical Practice Guidelines in Oncology for Chronic Myelogenous Leukemia recommend quantitative reverse-transcription polymerase chain reaction (QPCR) standardized to International Scale (IS) as the preferred method for monitoring molecular response to tyrosine kinase inhibitor (TKI) therapy. A BCR-ABL1 transcript level of 10% or less (IS) is now included as the response milestone at 3 and 6 months. Change of therapy to an alternate TKI is recommended for patients with BCR-ABL1 transcript levels greater than 10% (IS) at 3 months after primary treatment with imatinib. Continuing the same dose of TKI or switching to an alternate TKI are options for patients with BCR-ABL1 transcript levels greater than 10% (IS) at 3 months after primary treatment with dasatinib or nilotinib. The guidelines recommend 6-month evaluation with QPCR (IS) for patients with BCR-ABL1 transcript levels greater than 10% at 3 months. Monitoring with QPCR (IS) every 3 months is recommended for all patients, including those who meet response milestones at 3, 6, 12, and 18 months (BCR-ABL1 transcript level ≤10% [IS] at 3 and 6 months, complete cytogenetic response at 12 and 18 months).
- Published
- 2013
33. Validation of a Dysphagia Signature Using Unsupervised Cluster Analysis of the MD Anderson Dysphagia Inventory and the Sydney Swallow Questionnaire Confirms Three Unique Patient Groups
- Author
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L.C. Peng, Julia Maclean, Scott P. Robertson, Michal M. Szczesniak, M.R. Bowers, Ian J. Cook, Alexander Thompson, Brandi R. Page, Christine G. Gourin, Carole Fakhry, Todd McNutt, Xuan Hui, M. Muse, A. Choflet, Zhi Cheng, Joseph O. Moore, Ana P. Kiess, and Harry Quon
- Subjects
Cancer Research ,medicine.medical_specialty ,Radiation ,business.industry ,Disease cluster ,Sydney swallow questionnaire ,Dysphagia ,Oncology ,Physical therapy ,Medicine ,Radiology, Nuclear Medicine and imaging ,medicine.symptom ,business ,MD Anderson Dysphagia Inventory - Published
- 2017
34. PTV Hot-Spot Volume is Associated With Improved Pathologic Response After Neoadjuvant Stereotactic Body Radiation Therapy for Pancreatic Cancer
- Author
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J.M. Herman, L.M. Rosati, Li Chen, Amy Hacker-Prietz, Todd McNutt, P. Lakshminarayanan, Amol Narang, Zhi Cheng, and Joseph O. Moore
- Subjects
Oncology ,Cancer Research ,medicine.medical_specialty ,Radiation ,Stereotactic body radiation therapy ,business.industry ,Hot spot (veterinary medicine) ,medicine.disease ,Internal medicine ,Pancreatic cancer ,medicine ,Pathologic Response ,Radiology, Nuclear Medicine and imaging ,Radiology ,business ,Volume (compression) - Published
- 2017
35. Correlation of Functional Assessment of Cancer Therapy With the MD Anderson Dysphagia Inventory and the Sydney Swallow Questionnaire in a Prospective Cohort of Patients with Head and Neck Cancer
- Author
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Ian J. Cook, Todd McNutt, Michal M. Szczesniak, Julia Maclean, M. Muse, A. Choflet, Ana P. Kiess, Brandi R. Page, Harry Quon, Alexander Thompson, Carole Fakhry, Christine G. Gourin, Zhi Cheng, M.R. Bowers, Joseph O. Moore, Xuan Hui, and L.C. Peng
- Subjects
Cancer Research ,medicine.medical_specialty ,Radiation ,business.industry ,Head and neck cancer ,Cancer therapy ,Sydney swallow questionnaire ,medicine.disease ,Oncology ,Physical therapy ,Medicine ,Radiology, Nuclear Medicine and imaging ,business ,MD Anderson Dysphagia Inventory ,Prospective cohort study - Published
- 2017
36. Low Risk of Symptomatic Radionecrosis Following Stereotactic Radiosurgery for Multiple Brain Metastases
- Author
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D. Nikolaidis, Chetan Bettegowda, Ellen Huang, Colette J. Shen, Y. Seo, L. Chan, Sarah Z. Hazell, Michael Lim, Joseph O. Moore, L. Sloan, L.R. Kleinberg, K.J. Redmond, Harry Quon, and Jimm Grimm
- Subjects
Cancer Research ,medicine.medical_specialty ,Radiation ,business.industry ,medicine.medical_treatment ,Radiosurgery ,030218 nuclear medicine & medical imaging ,03 medical and health sciences ,0302 clinical medicine ,Oncology ,030220 oncology & carcinogenesis ,medicine ,Radiology, Nuclear Medicine and imaging ,Radiology ,business - Published
- 2017
37. Patients' Perspectives on the Definition of Cure in Chronic Myeloid Leukemia: A US Based Survey
- Author
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Gemlyn George, Javier Pinilla Ibarz, Alexander Hinman, Kathryn E. Flynn, Richard A. Larson, Charles A. Schiffer, Kendra Sweet, Michael J. Mauro, Brian J. Druker, Arielle Baim, James E. Thompson, Vamsi Kota, Jessica Guhl, Michael W. Deininger, Joseph O. Moore, Jorge E. Cortes, Jerald P. Radich, Richard T. Silver, Neil P. Shah, Martha Wadleigh, Jeffrey H. Lipton, Stuart L. Goldberg, Ehab Atallah, Vivian G. Oehler, and Ellen K. Ritchie
- Subjects
medicine.medical_specialty ,Intravenous treatment ,Patient demographics ,Immunology ,Cell Biology ,Hematology ,Biochemistry ,Disease control ,Chronic disease ,Informed consent ,Family medicine ,Respondent ,Honorarium ,medicine ,Patient survey ,Business - Abstract
Introduction: The development of tyrosine kinase inhibitors (TKIs) has markedly improved the prognosis of patients (pts) with chronic myeloid leukemia (CML), with the perception by healthcare professionals that this is now a chronic disease to be managed. However, the need for continuous TKI therapy may result in ongoing toxicities, limits on fertility, and financial hardship. The H. Jean Khoury Cure CML consortium (HJKC3) is a collaborative effort of physicians and researchers at 17 academic centers. The HJKC3-001 2017 Patient Survey sought to define pts' expectations for treatment in CML to serve as a guidepost for future research in this area. Methods: Pts with CML were recruited by HJKC3 physicians, CML advocacy groups, and social media. An online survey platform (Qualtrics®) was used to obtain informed consent and administer the questionnaire. The anonymous survey was designed to gauge priorities for research in CML, understand patient definitions of cure, and elicit patient interest in future directions for CML therapy. Patient demographic and health characteristics were also collected. The data were analyzed using descriptive statistics. Results: Of the 458 pts who completed the survey, the median age of respondents was 54 years (range 18-81); 88% of pts identified as non-Hispanic white, 2% as non-Hispanic black, 2% as non-Hispanic Asian, 4% as Hispanic, and 4% other. Patients rated their overall health as poor (4%), fair (18%), good (40%), very good (28%) and excellent (9%). All but one respondent said that more research was needed for CML, with pts indicating their preferences for where they considered the need was greatest (Table 1). Overwhelmingly, 94% of respondents considered cure in CML as not taking any more pills. All but three respondents had received treatment with a TKI, with 26% (n=119) of pts having previously stopped their TKI medication for at least one month. When presented with the possibility of stopping all future treatment for CML with additional treatment, 97% of pts were willing to add another oral medication to their TKI while 89% of pts would accept intravenous treatment in addition to a TKIs. Half of the pts had discussed treatment discontinuation with their physician, with 45% considering this option in an attempt at treatment-free-remission. Of the pts that stopped taking their TKIs for at least one month, 65% did so because of side effects and another 10% because of cost. Conclusion: This survey demonstrates that pts do not consider disease control with life-long oral medication as cure; rather, cure requires the absence of treatment. Overwhelmingly, pts indicated the importance of continuing CML research with an ultimate goal of treatment-free cure. The advent of oral TKIs has been a tremendous success for pts with this disease. Nevertheless, it remains a source of disruption in pts' lives, particularly through side effects and costs. The HJKC3 was initiated with the goal of curing CML. Disclosures Atallah: Novartis: Consultancy; Jazz: Consultancy; Pfizer: Consultancy; BMS: Consultancy; Abbvie: Consultancy. Mauro:Bristol-Myers Squibb: Consultancy; Pfizer: Consultancy; Takeda: Consultancy; Novartis: Consultancy, Research Funding. Goldberg:COTA Inc.: Employment, Equity Ownership. Cortes:Daiichi Sankyo: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Astellas Pharma: Consultancy, Research Funding; Arog: Research Funding. Deininger:Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Blueprint: Consultancy. Druker:ARIAD: Research Funding; Third Coast Therapeutics: Membership on an entity's Board of Directors or advisory committees; Patient True Talk: Consultancy; Amgen: Membership on an entity's Board of Directors or advisory committees; MolecularMD: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Novartis Pharmaceuticals: Research Funding; Henry Stewart Talks: Patents & Royalties; Leukemia & Lymphoma Society: Membership on an entity's Board of Directors or advisory committees, Research Funding; McGraw Hill: Patents & Royalties; Aptose Therapeutics: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Cepheid: Consultancy, Membership on an entity's Board of Directors or advisory committees; GRAIL: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol-Meyers Squibb: Research Funding; Oregon Health & Science University: Patents & Royalties; Gilead Sciences: Consultancy, Membership on an entity's Board of Directors or advisory committees; Monojul: Consultancy; Vivid Biosciences: Membership on an entity's Board of Directors or advisory committees; Blueprint Medicines: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Millipore: Patents & Royalties; Fred Hutchinson Cancer Research Center: Research Funding; Beta Cat: Membership on an entity's Board of Directors or advisory committees; ALLCRON: Consultancy, Membership on an entity's Board of Directors or advisory committees; Aileron Therapeutics: Consultancy; Celgene: Consultancy. Larson:Novartis: Consultancy, Research Funding; Ariad/Takeda: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; BristolMyers Squibb: Consultancy, Research Funding. Lipton:Bristol-Myers Squibb: Consultancy, Research Funding; ARIAD: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding. Ritchie:Incyte: Consultancy, Speakers Bureau; NS Pharma: Research Funding; Bristol-Myers Squibb: Research Funding; Astellas Pharma: Research Funding; ARIAD Pharmaceuticals: Speakers Bureau; Novartis: Consultancy, Other: Travel, Accommodations, Expenses, Research Funding, Speakers Bureau; Pfizer: Consultancy, Research Funding; Celgene: Consultancy, Other: Travel, Accommodations, Expenses, Speakers Bureau. Shah:Bristol-Myers Squibb: Research Funding; ARIAD: Research Funding. Sweet:Celgene: Honoraria, Speakers Bureau; Jazz: Speakers Bureau; Celgene: Honoraria, Speakers Bureau; Agios: Consultancy; Phizer: Consultancy; Astellas: Consultancy; Astellas: Consultancy; Jazz: Speakers Bureau; Phizer: Consultancy; BMS: Honoraria; Novartis: Consultancy, Honoraria, Speakers Bureau; Agios: Consultancy; Novartis: Consultancy, Honoraria, Speakers Bureau; BMS: Honoraria.
- Published
- 2018
38. Acute Myeloid Leukemia, Version 2.2013
- Author
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Martin S. Tallman, Eunice S. Wang, B. Douglas Smith, Kristina M. Gregory, Stephen A. Strickland, Frederick R. Appelbaum, Joseph O. Moore, Camille N. Abboud, Jessica K. Altman, Maoko Naganuma, Jeffrey E. Lancet, Guido Marcucci, Lloyd E. Damon, Eyal C. Attar, Lori J. Maness, Richard Stone, Uma Borate, Michael Millenson, Daniel A. Arber, Steven Coutre, Michael Gary Martin, Farhad Ravandi, Margaret R. O'Donnell, and Paul J. Shami
- Subjects
Acute promyelocytic leukemia ,medicine.medical_specialty ,Myeloid ,business.industry ,Myeloid leukemia ,medicine.disease ,Article ,Leukemia, Myeloid, Acute ,Leukemia ,medicine.anatomical_structure ,Leukemia, Promyelocytic, Acute ,Oncology ,immune system diseases ,Clinical evidence ,hemic and lymphatic diseases ,Antineoplastic Combined Chemotherapy Protocols ,Humans ,Medicine ,In patient ,business ,Intensive care medicine ,neoplasms - Abstract
These NCCN Guidelines Insights summarize several key updates to the NCCN Guidelines for Acute Myeloid Leukemia and discuss the clinical evidence that support the recommendations. The updates described in this article focus on the acute promyelocytic leukemia (APL) section, featuring recommendations for additional induction/consolidation regimens in patients with low- or intermediate-risk APL, and providing guidance on maintenance strategies for APL.
- Published
- 2013
39. Perifosine treatment in chronic lymphocytic leukemia: results of a phase II clinical trial andin vitrostudies
- Author
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Daphne R. Friedman, Evan D. Davis, Peter Sportelli, Mark C. Lanasa, Jon P. Gockerman, Patricia H. Davis, Karen M. Matta, J. Brice Weinberg, Alicia D. Volkheimer, Joseph O. Moore, Danielle M. Brander, Youwei Chen, and Sallie D. Allgood
- Subjects
Male ,Cancer Research ,Cell Survival ,Phosphorylcholine ,Chronic lymphocytic leukemia ,Antineoplastic Agents ,Pharmacology ,chemistry.chemical_compound ,In vivo ,hemic and lymphatic diseases ,medicine ,Humans ,Phosphorylation ,Protein kinase B ,PI3K/AKT/mTOR pathway ,Aged ,Neoplasm Staging ,Aged, 80 and over ,Dose-Response Relationship, Drug ,business.industry ,Hematology ,Middle Aged ,Perifosine ,medicine.disease ,Leukemia, Lymphocytic, Chronic, B-Cell ,Leukemia ,Treatment Outcome ,Oncology ,chemistry ,Cancer research ,Female ,business ,Proto-Oncogene Proteins c-akt ,Ex vivo ,Progressive disease ,Signal Transduction - Abstract
Because of the importance of the phosphoinositide 3-kinase (PI3K)/AKT pathway in chronic lymphocytic leukemia (CLL), we evaluated in vitro cytotoxicity induced by perifosine, an AKT inhibitor, in CLL lymphocytes and found that the mean 50% effective dose (ED50) was 313 nM. We then performed a phase II trial of perifosine in patients with relapsed/refractory CLL to assess response, outcomes, toxicity and ex vivo correlative measures. After 3 months of treatment, six of eight patients showed stable disease, one achieved a partial response and one had progressive disease. Median event-free survival and overall survival in all patients treated were 3.9 and 9.7 months. Adverse events included hematologic, infectious/fever, pain, gastrointestinal and constitutional toxicities. Unexpectedly, AKT phosphorylation in CLL lymphocytes from treated patients was not correlated with response. Additionally, perifosine did not inhibit AKT phosphorylation in cultured CLL lymphocytes. Perifosine is cytotoxic to CLL cells in vitro, and largely induces stabilized disease in vivo, with an AKT-independent mechanism.
- Published
- 2013
40. A Phase I Study of Arsenic Trioxide (Trisenox), Ascorbic Acid, and Bortezomib (Velcade) Combination Therapy in Patients With Relapsed/Refractory Multiple Myeloma
- Author
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Nelson J. Chao, Jon P. Gockerman, Cristina Gasparetto, Lauren A Held, Joseph O. Moore, David A. Rizzieri, Carlos M. de Castro, Louis F. Diehl, Mitchell E. Horwitz, and Gwynn D. Long
- Subjects
Male ,Cancer Research ,medicine.medical_specialty ,Combination therapy ,medicine.medical_treatment ,Population ,Ascorbic Acid ,Pharmacology ,Gastroenterology ,Arsenicals ,Bortezomib ,chemistry.chemical_compound ,Arsenic Trioxide ,Recurrence ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Humans ,Arsenic trioxide ,education ,Multiple myeloma ,Aged ,education.field_of_study ,Chemotherapy ,business.industry ,Oxides ,General Medicine ,Middle Aged ,medicine.disease ,Ascorbic acid ,Boronic Acids ,Oncology ,chemistry ,Pyrazines ,Concomitant ,Female ,Multiple Myeloma ,business ,medicine.drug - Abstract
Purpose: This Phase I study assessed the feasibility of concomitant arsenic trioxide (ATO), ascorbic acid (AA), and bortezomib (Velcade™) (AAV) for patients with relapsed/refractory multiple myeloma. Experimental Design: ATO (0.25 mg/kg) and AA (1 g) were given with an escalating dose of bortezomib (1 mg/m2 or 1.3 mg/m2 IV bolus on days 1 and 8 of a 21-day cycle). Results: Ten patients (median age 62 years), with a median of 3 prior regimens, were enrolled. Four (40%) patients achieved clinical benefit, with one patient achieving a durable partial response. No formal DLTs were encountered. Conclusion: AAV combination was feasible and demonstrated some benefits in this heavily pretreated population.
- Published
- 2013
41. Re-induction therapy decisions based on day 14 bone marrow biopsy in acute myeloid leukemia
- Author
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Anand S. Lagoo, Arati V. Rao, Zhiguo Li, Louis F. Diehl, Tod A. Morris, David A. Rizzieri, Joseph O. Moore, Jon P. Gockerman, and Carlos M. DeCastro
- Subjects
Adult ,Oncology ,Cancer Research ,Pathology ,medicine.medical_specialty ,Myeloid ,Adolescent ,Biopsy ,medicine.medical_treatment ,Article ,Bone Marrow ,hemic and lymphatic diseases ,Internal medicine ,medicine ,Humans ,Aged ,Retrospective Studies ,Chemotherapy ,medicine.diagnostic_test ,business.industry ,Induction chemotherapy ,Myeloid leukemia ,Retrospective cohort study ,Induction Chemotherapy ,Hematology ,Middle Aged ,medicine.disease ,Leukemia, Myeloid, Acute ,Leukemia ,medicine.anatomical_structure ,Bone marrow ,business - Abstract
The decision to re-induce patients with acute myeloid leukemia (AML) based on results of the day 14 bone marrow (BM) biopsy is variable and lacks evidence based data. The aim of our review was to evaluate the accuracy of a day 14 BM biopsy in determining the need for re-induction chemotherapy.Seventy-four patients with newly diagnosed de novo AML treated with induction chemotherapy were retrospectively reviewed for the purpose of evaluating treatment decisions and outcomes based on their day 14 BM biopsy. Response to therapy in this analysis was based on morphology alone.Of the 74 patients undergoing standard induction, 45 patients (61%) had no evidence of leukemia on their day 14 BM biopsy. Eighteen patients (24%) had definitive residual disease (RD), and 11 patient's (15%) were classified as indeterminate response (IR). Fifteen patients with RD and one with IR underwent re-induction chemotherapy. However, thirteen patients (3 RD and 10 IR) were observed until count recovery without any re-induction therapy. Eleven of these 13 patients who were observed eventually attained a morphologic complete remission (CR), including two patients with RD.A day 14 BM biopsy may have suboptimal sensitivity for the detection of residual leukemia. Some patients with an IR on day 14 may not require re-induction chemotherapy, but instead, may benefit from careful observation until count recovery to avoid the mortality and morbidity associated with re-induction chemotherapy.
- Published
- 2013
42. Treatment of adults with acute lymphoblastic leukemia: Do the specifics of the regimen matter?
- Author
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Karen Seiter, David W. Golde, Katherine S. Panageas, Steven Coutre, Joseph O. Moore, Peter Maslak, Gary J. Schiller, Nicole Lamanna, Mark Weiss, Matt Kalaycio, and Leonard T. Heffner
- Subjects
Adult ,Male ,Cancer Research ,medicine.medical_specialty ,Vincristine ,Adolescent ,Disease-Free Survival ,law.invention ,Young Adult ,Maintenance therapy ,Randomized controlled trial ,law ,Internal medicine ,Acute lymphocytic leukemia ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Humans ,Prospective Studies ,Prospective cohort study ,Survival rate ,Aged ,Mitoxantrone ,business.industry ,Remission Induction ,Middle Aged ,Precursor Cell Lymphoblastic Leukemia-Lymphoma ,medicine.disease ,Surgery ,Regimen ,Oncology ,Female ,business ,medicine.drug - Abstract
BACKGROUND: Induction therapy for adults with acute lymphoblastic leukemia (ALL) is similar across essentially all regimens, comprised of vincristine, corticosteroids, and anthracyclines intensified with cyclophosphamide, asparaginase, or both. Given the lack of randomized data, to date, no regimen has emerged as standard. The authors previously evaluated cytarabine 3 g/m2 daily for 5 days with mitoxantrone 80 mg/m2 (the ALL-2 regimen) as a novel induction regimen. Compared with historic controls, the ALL-2 regimen was superior in terms of incidence of complete remission, failure with resistant disease, and activity in patients with Philadelphia chromosome (Ph)-positive ALL. METHODS: The authors conducted a multicenter, prospective, randomized trial of the ALL-2 regimen compared with a standard 4-drug induction (the L-20 regimen). Patients also received consolidation, maintenance therapy, and central nervous system prophylaxis. The trial accrued patients from August 1996 to October 2004. RESULTS: The median follow-up for survivors was 7 years, and the median patient age was 43 years. Responses were evaluated in 164 patients. The treatment arms were balanced in terms of pretreatment characteristics. The frequency of complete remission for the ALL-2 regimen versus the L-20 regimen was 83% versus 71% (P = .06). More patients on the L-20 arm failed with resistant disease (21% vs 8%; P = .02). Induction deaths were comparable at 9% (ALL-2) versus 7% (L-20). The median survival was similar; and, at 5 years, the survival rate was 33% alive on the ALL-2 arm versus 27% on the L-20. CONCLUSIONS: Despite superior results of induction therapy with the ALL-2 regimen, this treatment did not improve long-term outcomes. When coupled to the reported experience of other studies in adults with ALL, the results of this randomized trial raise the possibility that ultimate outcomes in adult ALL may be independent of the specific regimen chosen. Cancer 2013. © 2012 American Cancer Society.
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- 2012
43. RUNX1 Mutations Are Associated With Poor Outcome in Younger and Older Patients With Cytogenetically Normal Acute Myeloid Leukemia and With Distinct Gene and MicroRNA Expression Signatures
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Michael D. Radmacher, Sebastian Schwind, Kati Maharry, Susan P. Whitman, Klaus H. Metzeler, Joseph O. Moore, Richard A. Larson, Deedra Nicolet, Meir Wetzler, Andrew J. Carroll, Heiko Becker, Krzysztof Mrózek, Jihane Khalife, Michael A. Caligiuri, Jessica Kohlschmidt, Maria R. Baer, Jonathan E. Kolitz, Bayard L. Powell, Guido Marcucci, Jason H. Mendler, Thomas H. Carter, and Clara D. Bloomfield
- Subjects
Male ,Oncology ,Cancer Research ,Time Factors ,DNA Mutational Analysis ,Kaplan-Meier Estimate ,Gene mutation ,medicine.disease_cause ,Polymerase Chain Reaction ,Risk Factors ,hemic and lymphatic diseases ,Antineoplastic Combined Chemotherapy Protocols ,CEBPA ,Oligonucleotide Array Sequence Analysis ,Aged, 80 and over ,Mutation ,Age Factors ,Middle Aged ,Gene Expression Regulation, Neoplastic ,Leukemia, Myeloid, Acute ,Leukemia ,Phenotype ,Treatment Outcome ,Core Binding Factor Alpha 2 Subunit ,Cytogenetic Analysis ,Disease Progression ,Female ,Nucleophosmin ,medicine.drug ,Adult ,NPM1 ,medicine.medical_specialty ,Adolescent ,Risk Assessment ,Disease-Free Survival ,Young Adult ,Internal medicine ,Original Reports ,medicine ,Humans ,Genetic Predisposition to Disease ,Aged ,Proportional Hazards Models ,business.industry ,Gene Expression Profiling ,Cancer ,medicine.disease ,United States ,Gene expression profiling ,MicroRNAs ,Logistic Models ,Multivariate Analysis ,Immunology ,Cytarabine ,business - Abstract
Purpose To determine the association of RUNX1 mutations with therapeutic outcome in younger and older patients with primary cytogenetically normal acute myeloid leukemia (CN-AML) and with gene/microRNA expression signatures. Patients and Methods Younger (< 60 years; n = 175) and older (≥ 60 years; n = 225) patients with CN-AML treated with intensive cytarabine/anthracycline-based first-line therapy on Cancer and Leukemia Group B protocols were centrally analyzed for RUNX1 mutations by polymerase chain reaction and direct sequencing and for established prognostic gene mutations. Gene/microRNA expression profiles were derived using microarrays. Results RUNX1 mutations were found in 8% and 16% of younger and older patients, respectively (P = .02). They were associated with ASXL1 mutations (P < .001) and inversely associated with NPM1 (P < .001) and CEBPA (P = .06) mutations. RUNX1-mutated patients had lower complete remission rates (P = .005 in younger; P = .006 in older) and shorter disease-free survival (P = .058 in younger; P < .001 in older), overall survival (P = .003 in younger; P < .001 in older), and event-free survival (P < .001 for younger and older) than RUNX1 wild-type patients. Because RUNX1 mutations were more common in older patients and almost never coexisted with NPM1 mutations, RUNX1 mutation–associated expression signatures were derived in older, NPM1 wild-type patients and featured upregulation of genes normally expressed in primitive hematopoietic cells and B-cell progenitors, including DNTT, BAALC, BLNK, CD109, RBPMS, and FLT3, and downregulation of promoters of myelopoiesis, including CEBPA and miR-223. Conclusion RUNX1 mutations are twice as common in older than younger patients with CN-AML and negatively impact outcome in both age groups. RUNX1-mutated blasts have molecular features of primitive hematopoietic and lymphoid progenitors, potentially leading to novel therapeutic approaches.
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- 2012
44. Chronic lymphocytic leukemia and regulatory B cells share IL-10 competence and immunosuppressive function
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Joseph O. Moore, Russell P. Hall, Takashi Matsushita, Mayuka Horikawa, Ayumi Yoshizaki, Louis F. Diehl, Daphne R. Friedman, Guglielmo M. Venturi, Karen M. Matta, David J. DiLillo, J M Bryant, Yohei Iwata, Thomas F. Tedder, JB Weinberg, Giandomenico Russo, Youwei Chen, Alicia D. Volkheimer, Jon P. Gockerman, and Mark C. Lanasa
- Subjects
Lipopolysaccharides ,Cancer Research ,Regulatory B cells ,Chronic lymphocytic leukemia ,Cell ,Fluorescent Antibody Technique ,Mice, Transgenic ,Biology ,Article ,Mice ,immune system diseases ,Proto-Oncogene Proteins ,hemic and lymphatic diseases ,medicine ,Animals ,Humans ,Cells, Cultured ,Immunosuppression Therapy ,B-Lymphocytes ,B-Lymphocytes, Regulatory ,Interleukin ,Hematology ,medicine.disease ,Leukemia, Lymphocytic, Chronic, B-Cell ,Interleukin-10 ,Leukemia ,Interleukin 10 ,medicine.anatomical_structure ,Oncology ,Immunology ,CD5 ,Ex vivo - Abstract
Chronic lymphocytic leukemia (CLL) can be immunosuppressive in humans and mice, and CLL cells share multiple phenotypic markers with regulatory B cells that are competent to produce interleukin (IL)-10 (B10 cells). To identify functional links between CLL cells and regulatory B10 cells, the phenotypes and abilities of leukemia cells from 93 patients with overt CLL to express IL-10 were assessed. CD5(+) CLL cells purified from 90% of the patients were IL-10-competent and secreted IL-10 following appropriate ex vivo stimulation. Serum IL-10 levels were also significantly elevated in CLL patients. IL-10-competent cell frequencies were higher among CLLs with IgV(H) mutations, and correlated positively with TCL1 expression. In the TCL1-transgenic (TCL1-Tg) mouse model of CLL, IL-10-competent B cells with the cell surface phenotype of B10 cells expanded significantly with age, preceding the development of overt, CLL-like leukemia. Malignant CLL cells in TCL1-Tg mice also shared immunoregulatory functions with mouse and human B10 cells. Serum IL-10 levels varied in TCL1-Tg mice, but in vivo low-dose lipopolysaccharide treatment induced IL-10 expression in CLL cells and high levels of serum IL-10. Thus, malignant IL-10-competent CLL cells exhibit regulatory functions comparable to normal B10 cells that may contribute to the immunosuppression observed in patients and TCL1-Tg mice.
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- 2012
45. miR-3151 interplays with its host gene BAALC and independently affects outcome of patients with cytogenetically normal acute myeloid leukemia
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Michael D. Radmacher, Bayard L. Powell, Guido Marcucci, Meir Wetzler, Heiko Becker, Kati Maharry, Richard A. Larson, Jonathan E. Kolitz, Deedra Nicolet, Clara D. Bloomfield, Michael A. Caligiuri, Sandya Liyanarachchi, Sebastian Schwind, Krzysztof Mrózek, Yue-Zhong Wu, Albert de la Chapelle, Susan P. Whitman, Ann-Kathrin Eisfeld, Stephan M. Tanner, Ravi Patel, Klaus H. Metzeler, Joseph O. Moore, Jason H. Mendler, Thomas H. Carter, and Maria R. Baer
- Subjects
Male ,Myeloid ,Immunology ,Gene Expression ,Kaplan-Meier Estimate ,Biology ,Bioinformatics ,Biochemistry ,Disease-Free Survival ,microRNA ,Gene expression ,medicine ,Humans ,RNA, Neoplasm ,Gene ,BAALC ,Aged ,Aged, 80 and over ,F-Box Proteins ,Cell Biology ,Hematology ,Middle Aged ,Prognosis ,medicine.disease ,Neoplasm Proteins ,Gene expression profiling ,Leukemia, Myeloid, Acute ,MicroRNAs ,Leukemia ,medicine.anatomical_structure ,Cytogenetic Analysis ,Cancer research ,Female ,DNA microarray ,Ubiquitin Thiolesterase - Abstract
High BAALC expression levels are associated with poor outcome in cytogenetically normal acute myeloid leukemia (CN-AML) patients. Recently, miR-3151 was discovered in intron 1 of BAALC. To evaluate the prognostic significance of miR-3151 expression levels and to gain insight into the biologic and prognostic interplay between miR-3151 and its host, miR-3151 and BAALC expression were measured in pretreatment blood of 179 CN-AML patients. Gene-expression profiling and miRNA-expression profiling were performed using microarrays. High miR-3151 expression was associated with shorter disease-free and overall survival, whereas high BAALC expression predicted failure of complete remission and shorter overall survival. Patients exhibiting high expression of both miR-3151 and BAALC had worse outcome than patients expressing low levels of either gene or both genes. In gene-expression profiling, high miR-3151 expressers showed down-regulation of genes involved in transcriptional regulation, posttranslational modification, and cancer pathways. Two genes, FBXL20 and USP40, were validated as direct miR-3151 targets. The results of the present study show that high expression of miR-3151 is an independent prognosticator for poor outcome in CN-AML and affects different outcome end points than its host gene, BAALC. The combination of both markers identified a patient subset with the poorest outcome. This interplay between an intronic miR and its host may have important biologic implications.
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- 2012
46. Phase I study of dose dense induction and consolidation with gemtuzumab ozogamicin and high dose cytarabine in older adults with AML
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Arati V. Rao, Anand S. Lagoo, David A. Rizzieri, Jon P. Gockerman, Louis F. Diehl, Joseph O. Moore, and Carlos M. DeCastro
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Oncology ,Chemotherapy ,medicine.medical_specialty ,business.industry ,Gemtuzumab ozogamicin ,medicine.medical_treatment ,CD33 ,Myeloid leukemia ,medicine.disease ,Pancytopenia ,Targeted therapy ,Surgery ,Internal medicine ,Toxicity ,Cohort ,Medicine ,Geriatrics and Gerontology ,business ,medicine.drug - Abstract
Objective Older adults with acute myeloid leukemia (AML) tend to have worse complete remission (CR) rates and overall survival compared to their younger counterparts. At least one reason for this is increased expression of the multidrug resistance gene (MDR1). Dose dense, high intensity chemotherapy may overcome the MDR1 effect, possibly when combined with anti-CD33 monoclonal antibody gemtuzumab ozogamicin (GO,Mylotarg™), which has been studied in older adults with relapsed AML. This phase I study was aimed at establishing safety by defining a maximum tolerated dose (MTD) by treating older AML patients with two cycles of dose-dense therapy with high dose cytarabine (HiDAC) combined with targeted therapy using GO. Materials and methods Nine patients ≥60years with newly diagnosed, untreated CD33+ AML with adequate renal and hepatic function, and ECOG PS 0-2 were eligible. HiDAC was administered at two dose levels: 3000mg/m 2 every 12h for 6 doses (cohort 1), or 9 doses (cohort 2). GO was administered at 6mg/m 2 on days 1 and 8. Results The MTD was HiDAC 3000mg/m 2 for six doses along with GO 6mg/m 2 . All patients had grades 3–4 pancytopenia, and two patients developed reversible grade 2 neurotoxicity. There were no cases of veno-occlusive disease. Seven of nine patients had a complete response (CR or CRp). Conclusions There was no difference in relapse-free survival in our patients when compared to historical data. However, despite high toxicity, two of nine patients treated in this dose-dense fashion remained in CR for >60months.
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- 2012
47. Hodgkin Lymphoma, Version 2.2012 Featured Updates to the NCCN Guidelines
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Weiyun Z. Ai, Peter Mauch, Craig H. Moskowitz, Joachim Yahalom, David G. Maloney, Joseph O. Moore, Kristie A. Blum, Patricia Aoun, David B. Mansur, Robert T. Chen, Andres Forero, Richard T. Hoppe, Bouthaina S. Dabaja, Celeste M. Bello, Richard F. Ambinder, Philip J. Bierman, Hema Sundar, Ysabel Duron, Leo I. Gordon, Ephraim P. Hochberg, Jane N. Winter, Matthew M. Poppe, Ranjana H. Advani, Barbara Pro, David S. Morgan, Francisco J. Hernandez-Ilizaliturri, and Monika L. Metzger
- Subjects
Oncology ,medicine.medical_specialty ,Chemotherapy ,business.industry ,medicine.medical_treatment ,Antineoplastic Agents ,RELAPSED DISEASE ,Medical Oncology ,medicine.disease ,Hodgkin Disease ,Positron-Emission Tomography ,Internal medicine ,Interim ,medicine ,Humans ,Hodgkin lymphoma ,Rituximab ,Stage (cooking) ,Brentuximab vedotin ,business ,Progressive disease ,Neoplasm Staging ,medicine.drug - Abstract
The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Hodgkin Lymphoma (HL) include the clinical management of classical HL and lymphocyte-predominant HL (LPHL). Major changes have been incorporated into these guidelines since their inception. In the 2012 NCCN Guidelines for HL, PET scans are not recommended for interim restaging of patients with stage I to II favorable disease. After reevaluating the available evidence on the use of interim PET imaging, the panel recommends the use of diagnostic CT scan of involved sites for interim restaging after completion of chemotherapy for this group of patients. Maintenance rituximab for 2 years is included as an option for patients with stage IB to IIB or stage III to IV LPHL treated with rituximab alone in the first-line setting. Brentuximab vedotin is included as an option for patients with progressive disease or relapsed disease after second-line chemotherapy or high-dose therapy with autologous stem cell rescue.
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- 2012
48. SET oncoprotein overexpression in B-cell chronic lymphocytic leukemia and non-Hodgkin lymphoma: a predictor of aggressive disease and a new treatment target
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Jessica Neil, Michael P. Vitek, J. Brice Weinberg, Carlos M. de Castro, Evan D. Davis, Alicia D. Volkheimer, Youwei Chen, Louis F. Diehl, Jon P. Gockerman, Dale J. Christensen, Jessica Oddo, Daphne R. Friedman, Joseph O. Moore, Barbara K. Goodman, Mark C. Lanasa, and Karen M. Matta
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Male ,Clinical Trials and Observations ,Chronic lymphocytic leukemia ,Immunology ,Mice, SCID ,Biology ,Biochemistry ,Mice ,BCL9 ,immune system diseases ,Cell Line, Tumor ,hemic and lymphatic diseases ,medicine ,Animals ,Humans ,Cytotoxic T cell ,Histone Chaperones ,Protein Phosphatase 2 ,neoplasms ,Gene Expression Regulation, Leukemic ,Lymphoma, Non-Hodgkin ,Cancer ,Cell Biology ,Hematology ,medicine.disease ,Leukemia, Lymphocytic, Chronic, B-Cell ,Xenograft Model Antitumor Assays ,Lymphoma ,DNA-Binding Proteins ,Myeloid Cell Leukemia Sequence 1 Protein ,Leukemia ,Proto-Oncogene Proteins c-bcl-2 ,Apoptosis ,Cancer research ,Peptides ,Transcription Factors - Abstract
B-cell chronic lymphocytic leukemia (CLL), an incurable leukemia, is characterized by defective apoptosis. We found that the SET oncoprotein, a potent inhibitor of the protein phosphatase 2A (PP2A) tumor suppressor, is overexpressed in primary CLL cells and B-cell non-Hodgkin lymphoma (NHL) cell line cells. In CLL, increased levels of SET correlated significantly with disease severity (shorter time to treatment and overall survival). We developed SET antagonist peptides that bound SET, increased cellular PP2A activity, decreased Mcl-1 expression, and displayed selective cytotoxicity for CLL and NHL cells in vitro. In addition, shRNA for SET was cytotoxic for NHL cells in vitro. The SET antagonist peptide COG449 inhibited growth of NHL tumor xenografts in mice. These data demonstrate that SET is a new treatment target in B-cell malignancies and that SET antagonists represent novel agents for treatment of CLL and NHL.
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- 2011
49. Phase II study of cenersen, an antisense inhibitor of p53, in combination with fludarabine, cyclophosphamide and rituximab for high-risk chronic lymphocytic leukemia
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Mark C. Lanasa, Catherine Rehder, Michael B. Datto, Jon P. Gockerman, Zhiguo Li, Louis F. Diehl, Harry Cook, Joseph O. Moore, David A. Rizzieri, Carlos M. DeCastro, J. Brice Weinberg, F Joseph Daugherty, Karen M. Matta, Daphne R. Friedman, and Patricia H. Davis
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Male ,Oncology ,Cancer Research ,medicine.medical_specialty ,Cyclophosphamide ,Chronic lymphocytic leukemia ,Oligonucleotides ,Pharmacology ,Neutropenia ,Antibodies, Monoclonal, Murine-Derived ,Risk Factors ,hemic and lymphatic diseases ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Humans ,Survival rate ,Aged ,business.industry ,Hematology ,Middle Aged ,Prognosis ,medicine.disease ,Leukemia, Lymphocytic, Chronic, B-Cell ,Fludarabine ,Survival Rate ,Leukemia ,Mutation ,Female ,Rituximab ,Tumor Suppressor Protein p53 ,business ,Vidarabine ,Follow-Up Studies ,Lymphoid leukemia ,medicine.drug - Abstract
Patients with chronic lymphocytic leukemia (CLL) with deletion or mutation of TP53 have exceedingly poor clinical outcomes. Cenersen, an oligonucleotide targeting TP53, has been shown to abrogate the activity of TP53 gain-of-function mutants and to increase sensitivity of lymphoma cells to cytotoxic chemotherapy in vitro. We combined cenersen with fludarabine, cyclophosphamide and rituximab (FCR) as treatment for patients with high-risk CLL. The purpose of this phase II study was to determine the overall response rate, response duration and toxicity of cenersen administered in combination with FCR. Twenty patients with relapsed or high-risk CLL were evaluated. Nineteen patients were previously treated. The complete response rate was 18%; the overall response rate was 53%. Median progression-free and overall survival was 5.3 and 10.6 months, respectively. The most common serious adverse events were neutropenia and thrombocytopenia. In this single arm phase II study, cenersen combined with FCR yielded clinical responses with acceptable toxicity in patients with high-risk CLL.
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- 2011
50. Hodgkin Lymphoma
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Richard T, Hoppe, Ranjana H, Advani, Weiyun Z, Ai, Richard F, Ambinder, Celeste M, Bello, Philip J, Bierman, Kristie A, Blum, Bouthaina, Dabaja, Ysabel, Duron, Andres, Forero, Leo I, Gordon, Francisco J, Hernandez-Ilizaliturri, Ephraim P, Hochberg, David G, Maloney, David, Mansur, Peter M, Mauch, Monika, Metzger, Joseph O, Moore, David, Morgan, Craig H, Moskowitz, Matthew, Poppe, Barbara, Pro, Lawrence, Weiss, Jane N, Winter, Joachim, Yahalom, and Robert H, Lurie
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Radiotherapy ,Oncology ,Recurrence ,Antineoplastic Combined Chemotherapy Protocols ,Disease Progression ,Humans ,Prognosis ,Watchful Waiting ,Combined Modality Therapy ,Hodgkin Disease ,Neoplasm Staging - Published
- 2011
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