7 results on '"Douglas Smith, B."'
Search Results
2. A Phase 1 Study of IRX195183, a RARα-Selective CYP26 Resistant Retinoid, in Patients With Relapsed or Refractory AML.
- Author
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Ambinder AJ, Norsworthy K, Hernandez D, Palau L, Paun B, Duffield A, Chandraratna R, Sanders M, Varadhan R, Jones RJ, Douglas Smith B, and Ghiaur G
- Abstract
Subsets of non-acute promyelocytic leukemia (APL) acute myelogenous leukemia (AML) exhibit aberrant retinoid signaling and demonstrate sensitivity to retinoids in vitro . We present the results of a phase 1 dose-escalation study that evaluated the safety, pharmacodynamics, and efficacy of IRX195183, a novel retinoic acid receptor α agonist, in patients with relapsed or refractory myelodysplastic syndrome (MDS) or AML. In this single center, single arm study, eleven patients with relapsed or refractory MDS/AML were enrolled and treated. Oral IRX195183 was administered at two dose levels: 50 mg daily or 75 mg daily for a total of two 28-day cycles. Patients with stable disease or better were allowed to continue on the drug for four additional 28-day cycles. Common adverse events included hypertriglyceridemia, fatigue, dyspnea, and edema. Three patients at the first dose level developed asymptomatic Grade 3 hypertriglyceridemia. The maximally tolerated dose was not reached. Four of the eleven patients had (36%) stable disease or better. One had a morphological complete remission with incomplete hematologic recovery while on the study drug. Two patients had evidence of in vivo leukemic blast maturation, as reflected by increased CD38 expression. In a pharmacodynamics study, plasma samples from four patients treated at the lowest dose level demonstrated the capacity to differentiate leukemic cells from the NB4 cell line in vitro . These results suggest that IRX195183 is safe, achieves biologically meaningful plasma concentrations and may be efficacious in a subset of patients with MDS/AML. Clinical Trial Registration: clinicaltrials.gov, identifier NCT02749708., (Copyright © 2020 Ambinder, Norsworthy, Hernandez, Palau, Paun, Duffield, Chandraratna, Sanders, Varadhan, Jones, Douglas Smith and Ghiaur.)
- Published
- 2020
- Full Text
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3. Immunomodulation with pomalidomide at early lymphocyte recovery after induction chemotherapy in newly diagnosed AML and high-risk MDS.
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Zeidner JF, Knaus HA, Zeidan AM, Blackford AL, Montiel-Esparza R, Hackl H, Prince GT, Gondek LP, Ghiaur G, Showel MM, DeZern AE, Pratz KW, Douglas Smith B, Levis MJ, Gore S, Coombs CC, Foster MC, Streicher H, Karp JE, Luznik L, and Gojo I
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- Adult, Aged, Cytarabine administration & dosage, Disease-Free Survival, Etoposide administration & dosage, Female, Hexosamines administration & dosage, Humans, Immunomodulation drug effects, Induction Chemotherapy methods, Male, Maximum Tolerated Dose, Middle Aged, Remission Induction, Thalidomide administration & dosage, Treatment Outcome, Young Adult, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Immunologic Factors administration & dosage, Leukemia, Myeloid, Acute drug therapy, Myelodysplastic Syndromes drug therapy, Thalidomide analogs & derivatives
- Abstract
An immunosuppressive microenvironment promoting leukemia cell immune escape plays an important role in the pathogenesis of AML. Through its interaction with cereblon, a substrate receptor for the E3 ubiquitin ligase complex, pomalidomide leads to selective ubiquitination of transcription factors Aiolos and Ikaros thereby promoting immune modulation. In this phase I trial, 51 newly diagnosed non-favorable risk AML and high-risk MDS patients were enrolled and treated with AcDVP16 (cytarabine 667 mg/m
2 /day IV continuous infusion days 1-3, daunorubicin 45 mg/m2 IV days 1-3, etoposide 400 mg/m2 IV days 8-10) induction therapy followed by dose- and duration-escalation pomalidomide beginning at early lymphocyte recovery. Forty-three patients (AML: n = 39, MDS: n = 4) received pomalidomide. The maximum tolerated dose of pomalidomide was 4 mg for 21 consecutive days. The overall complete remission (CR + CRi) rate, median overall survival, and disease-free survival were 75%, 27.1 and 20.6 months, respectively. Subset analyses revealed 86% CR/CRi rate in AML patients with unfavorable-risk karyotype treated with pomalidomide. Pomalidomide significantly decreased Aiolos expression in both CD4+ and CD8+ peripheral blood and bone marrow T cells, promoted T cell differentiation, proliferation, and heightened their cytokine production. Finally, pomalidomide induced distinct gene expression changes in immune function-related ontologies in CD4+ and CD8+ T cells.- Published
- 2020
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4. Matching-adjusted indirect comparison of bosutinib, dasatinib and nilotinib effect on survival and major cytogenetic response in treatment of second-line chronic phase chronic myeloid leukemia.
- Author
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Cortes JE, Muresan B, Mamolo C, Cappelleri JC, Crescenzo RJ, Su Y, Gambacorti-Passerini C, Heeg B, and Douglas Smith B
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- Cytogenetic Analysis, Female, Humans, Leukemia, Myeloid, Chronic-Phase genetics, Leukemia, Myeloid, Chronic-Phase mortality, Male, Middle Aged, Progression-Free Survival, Aniline Compounds therapeutic use, Dasatinib therapeutic use, Leukemia, Myeloid, Chronic-Phase drug therapy, Nitriles therapeutic use, Pyrimidines therapeutic use, Quinolines therapeutic use
- Abstract
Objective: In clinical trials of second-line therapies for chronic phase chronic myeloid leukemia (CP-CML), to date, only single-arm trials have been conducted for the available tyrosine kinase inhibitor treatments (bosutinib, dasatinib and nilotinib). These trials included heterogeneous patient populations in terms of disease and baseline characteristics. These hamper the use of standard network meta-analyses for indirect treatment comparison of relative efficacy. In this situation, a matching-adjusted indirect comparison (MAIC) in second-line CP-CML was performed. The aim was to compare the relative efficacies of bosutinib, dasatinib and nilotinib in second-line CP-CML patients. Methods: The MAIC was preceded by a systematic literature review that ensured inclusion of the underlying data for the analyses. The outcomes were measured in terms of overall survival (OS), progression-free survival (PFS) and major cytogenetic response (MCyR). The treatments were quantitatively compared based on Cox proportional hazard ratio (HR) regressions, on restricted mean survival (RMST, when the proportionality assumption showed evidence of violation) and on odds ratios (for response measures). Results: Comparing with dasatinib, bosutinib resulted in HRs for PFS and OS of 0.63 (0.44-0.90, p < .05) and 0.82 (0.54-1.26, p = .37) respectively, and resulted in an OR for MCyR of 0.78 (0.53-1.16). Although the proportionality of hazards assumption was violated for PFS, the RMST analyses confirmed the findings of the Cox regression. When compared with nilotinib, bosutinib showed a significant HR of 0.54 (0.38-0.76, p < .01) in favor of bosutinib for PFS, a non-significant HR of 0.72 (0.46-1.13, p = .16) for OS and a non-significant OR of 0.98 (0.71-1.35) for MCyR. Conclusions: Bosutinib had a significantly greater PFS than both dasatinib and nilotinib. For OS, the findings were numerically in favor of bosutinib, but not statistically significant. For MCyR, the findings were numerically in favor of dasatinib and nilotinib, but not statistically significant.
- Published
- 2019
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5. Glasdegib in combination with cytarabine and daunorubicin in patients with AML or high-risk MDS: Phase 2 study results.
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Cortes JE, Douglas Smith B, Wang ES, Merchant A, Oehler VG, Arellano M, DeAngelo DJ, Pollyea DA, Sekeres MA, Robak T, Ma WW, Zeremski M, Naveed Shaik M, Douglas Laird A, O'Connell A, Chan G, and Schroeder MA
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- Adult, Aged, Antineoplastic Combined Chemotherapy Protocols adverse effects, Consolidation Chemotherapy methods, Cytarabine administration & dosage, Daunorubicin administration & dosage, Female, Humans, Leukemia, Myeloid, Acute complications, Maintenance Chemotherapy methods, Male, Middle Aged, Myelodysplastic Syndromes complications, Remission Induction methods, Treatment Outcome, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Benzimidazoles administration & dosage, Leukemia, Myeloid, Acute drug therapy, Myelodysplastic Syndromes drug therapy, Phenylurea Compounds administration & dosage
- Abstract
Glasdegib is a Hedgehog pathway inhibitor. This ongoing, open-label, phase 2 study (NCT01546038) evaluated glasdegib plus cytarabine/daunorubicin in patients with untreated acute myeloid leukemia (AML) or high-risk myelodysplastic syndromes (MDS). Patients received glasdegib 100 mg orally, once daily in continuous 28-day cycles from day -3, with intravenous cytarabine 100 mg/m
2 on days 1-7 and daunorubicin 60 mg/m2 on days 1-3. Patients in remission then received consolidation therapy (2-4 cycles of cytarabine 1 g/m2 twice daily on days 1, 3, 5 of each cycle), followed by maintenance glasdegib (maximum 6 cycles). Primary endpoint was complete remission (CR) in patients aged ≥55 years. Secondary endpoints included overall survival (OS), safety and outcome by mutational status. Patients had a median (range) age of 64.0 (27-75) years, 60.0% were male, and 84.5% were white. In 69 evaluable patients, 46.4% (80% confidence interval [CI]: 38.7-54.1) achieved investigator-reported CR. Among patients ≥55 years old (n = 60), 40.0% (80% CI 31.9-48.1) achieved CR. Among all 69 patients, median OS was 14.9 (80% CI 13.4-19.3) months, with 12-month survival probability 66.6% (80% CI 58.5-73.4). The most common treatment-related adverse events (≥50% patients) were diarrhea and nausea. There were no significant associations between mutational status (12 genes) and clinical response, suggesting potential benefit across diverse molecular profiles. Glasdegib plus cytarabine/daunorubicin was well tolerated and associated with clinical activity in patients with untreated AML or high-risk MDS. A randomized phase 3 trial of glasdegib in combination with chemotherapy (7 + 3 schedule) is ongoing., (© 2018 The Authors. American Journal of Hematology published by Wiley Periodicals, Inc.)- Published
- 2018
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6. Myelodysplastic syndromes: what do hospitalists need to know?
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Zeidan AM, Faltas B, Douglas Smith B, and Gore S
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- Humans, Myelodysplastic Syndromes epidemiology, Clinical Competence standards, Hospitalists standards, Myelodysplastic Syndromes diagnosis, Myelodysplastic Syndromes therapy
- Abstract
Myelodysplastic syndromes (MDS) comprise a heterogeneous group of clonal hematopoietic stem cell disorders characterized by dysplasia, ineffective hematopoiesis leading to peripheral blood cytopenias, and a variable risk of leukemic progression. MDS primarily affects the elderly, and although its prevalence is increasing, MDS is frequently overlooked and underdiagnosed. MDS should be suspected in any patient with unexplained cytopenias, and a bone marrow evaluation is ultimately needed to make the diagnosis and exclude other causes of bone marrow failure. The last 15 years have witnessed significant advances in our understanding of the complex pathogenesis, classification and prognostication, and therapeutic approaches to MDS. Several prognostic models facilitate outcome prediction and risk-adapted therapy. The addition of azacitidine, decitabine, and lenalidomide to erythropoiesis-stimulating agents in our armamentarium offered new effective therapeutic options for many patients who are not candidates for intensive interventions. Improved understanding of the genetic, epigenetic, and immunologic mechanisms that operate in MDS will help develop better prognostication tools and rationally design more effective therapies. Hospitalists are likely to encounter both patients with MDS and patients in whom MDS should be suspected. In this review of MDS, we focus on the epidemiology, diagnosis, pathogenesis, classification and prognostic tools, and treatment options., (Copyright © 2013 Society of Hospital Medicine.)
- Published
- 2013
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7. An empirical study of religious mysticism.
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Douglas-Smith B
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- Adolescent, Adult, Age Factors, Aged, Child, Child, Preschool, Female, Humans, Intelligence, Male, Middle Aged, Neurotic Disorders, Psychotic Disorders, Religion, Social Class, Suggestion, Mysticism
- Published
- 1971
- Full Text
- View/download PDF
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