17 results on '"David F. Claxton"'
Search Results
2. Acute Myeloid Leukemia Stem Cells: Origin, Characteristics, and Clinical Implications
- Author
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Nathaniel A. Long, Upendarrao Golla, Arati Sharma, and David F. Claxton
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- 2022
3. Post-transplant cyclophosphamide alters immune signatures and leads to impaired T cell reconstitution in allogeneic hematopoietic stem cell transplant
- Author
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Chenchen Zhao, Matthew Bartock, Bei Jia, Neal Shah, David F. Claxton, Baldeep Wirk, Kevin L. Rakszawski, Myles S. Nickolich, Seema G. Naik, Witold B. Rybka, W Christopher C. Ehmann, Raymond J. Hohl, Jessica Valentin, Michelle Bernas-Peterson, Emily M. Gerber, Michele Zimmerman, Joseph A. Mierski, Shin Mineishi, and Hong Zheng
- Subjects
Cancer Research ,Oncology ,Programmed Cell Death 1 Receptor ,Hematopoietic Stem Cell Transplantation ,Graft vs Host Disease ,Humans ,Hematology ,CD8-Positive T-Lymphocytes ,Cyclophosphamide ,Molecular Biology - Abstract
Despite the increased usage of post-transplant cyclophosphamide (PTCy) in allogeneic hematopoietic stem cell transplantation (allo-HSCT), our knowledge of immune reconstitution post-allo-HSCT in the setting of PTCy is limited. Adequate immune reconstitution is the key to a successful transplant. In this study, we aim to investigate the effect of PTCy on the reconstitution of each immune component; more focus was placed on the immunophenotype and functions of T cells. Using blood samples from patients who underwent allo-HSCT under regimens containing PTCy (n = 23) versus those who received no PTCy (n = 14), we examined the impact of PTCy on the post-transplant immune response. We demonstrated a distinct T cell immune signature between PTCy versus non-PTCy group. PTCy significantly delayed T cell reconstitution and affected the T cell subsets by increasing regulatory T cells (Treg) while reducing naïve T cells. In addition, we observed remarkable enhancement of multiple inhibitory receptors (TIGIT, PD-1, TIM-3, CD38, CD39) on both CD4+ and CD8+ T cells on day 30 post-transplantation in patients who received PTCy. Importantly, upregulation of PD-1 on CD8 T cells was persistent through day 180 and these T cells were less functional, manifested by reduced cytokine production upon anti-CD3/CD28 stimulation. Furthermore, we found a significant correlation of T cell immune phenotypes to clinical outcome (disease relapse and GVHD) in patients who received PTCy. Our novel findings provide critical information to understand the mechanism of how PTCy impacts immune reconstitution in allo-HSCT and may subsequently lead to optimization of our clinical practice using this treatment.
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- 2022
4. Clofarabine followed by haploidentical stem cell transplant using fludarabine, busulfan, and total-body irradiation with post-transplant cyclophosphamide in non-remission AML
- Author
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Kosuke Miki, Kevin Rakszawski, Shin Mineishi, Seema Naik, Henry N. Wagner, David F. Claxton, and Hiroko Shike
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Adult ,Male ,Oncology ,medicine.medical_specialty ,Transplantation Conditioning ,medicine.medical_treatment ,Hematopoietic stem cell transplantation ,03 medical and health sciences ,0302 clinical medicine ,Adenine nucleotide ,hemic and lymphatic diseases ,Internal medicine ,Humans ,Medicine ,Clofarabine ,Busulfan ,Cyclophosphamide ,Adenine Nucleotides ,business.industry ,Remission Induction ,Hematopoietic Stem Cell Transplantation ,Hematology ,Total body irradiation ,Combined Modality Therapy ,Tumor Burden ,Fludarabine ,Transplantation ,Leukemia, Myeloid, Acute ,Treatment Outcome ,surgical procedures, operative ,030220 oncology & carcinogenesis ,Transplantation, Haploidentical ,Arabinonucleosides ,business ,Immunosuppressive Agents ,Vidarabine ,030215 immunology ,medicine.drug - Abstract
Approximately 30-40% of patients with acute myeloid leukemia (AML) experience induction failures. In these patients who do not achieve remission with two cycles of standard induction therapies, the probability of achieving remission with subsequent inductions is very limited. Hematopoietic stem cell transplantation (HSCT) is the only curative option for these patients, but high relapse rate and transplant-related mortality often preclude them to proceed to transplant. Thus, AML not in remission at time of HSCT remains a huge unmet need in current HSCT practice, particularly if the patient does not have an HLA-matched donor identified by the time of two induction failures. We used clofarabine cytoreduction immediately followed by fludarabine (Flu) and busulfan (Bu) × 3 with total-body irradiation (TBI) conditioning (Flu/Bu3/TBI) for haploidentical peripheral blood stem cell transplant with post-transplant cyclophosphamide for two cases of refractory AML with a very high tumor burden at transplant and achieved complete remission by day + 30 in both cases.
- Published
- 2018
5. Bone marrow CD8 T cells express high frequency of PD-1 and exhibit reduced anti-leukemia response in newly diagnosed AML patients
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Witold B. Rybka, Shin Mineishi, Todd D. Schell, Bei Jia, Hong Zheng, Michael G. Bayerl, W. Christopher Ehmann, David F. Claxton, Hiroko Shike, Raymond J. Hohl, Syed Rizvi, and Liru Wang
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Male ,0301 basic medicine ,Programmed Cell Death 1 Receptor ,Gene Expression ,Bone Marrow Cells ,Newly diagnosed ,CD8-Positive T-Lymphocytes ,lcsh:RC254-282 ,03 medical and health sciences ,0302 clinical medicine ,Text mining ,Correspondence ,Gene expression ,medicine ,Humans ,Cytotoxic T cell ,business.industry ,Hematology ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,medicine.disease ,Immunohistochemistry ,Leukemia, Myeloid, Acute ,Leukemia ,030104 developmental biology ,medicine.anatomical_structure ,Oncology ,030220 oncology & carcinogenesis ,Cancer research ,Female ,Bone marrow ,business - Published
- 2018
6. STAT3 mediates C6-ceramide-induced cell death in chronic lymphocytic leukemia
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Ushma A. Doshi, David F. Claxton, Mark Kester, Thomas P. Loughran, Todd E. Fox, and Jeremy Joseph Porter Shaw
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0301 basic medicine ,Cancer Research ,Ceramide ,Chronic lymphocytic leukemia ,Article ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,immune system diseases ,hemic and lymphatic diseases ,Survivin ,Genetics ,medicine ,Bruton's tyrosine kinase ,CD20 ,biology ,Kinase ,medicine.disease ,3. Good health ,030104 developmental biology ,chemistry ,030220 oncology & carcinogenesis ,Ibrutinib ,Cancer research ,biology.protein ,Signal transduction - Abstract
The pathogenesis of chronic lymphocytic leukemia (CLL) is poorly understood and it remains incurable with current therapies. We have previously shown that nanoliposomal C6-ceramide (CNL) is an effective therapy in an in vivo murine model of CLL. However, the key signaling pathways mediating CNL-induced cell death in CLL remains unknown. We hypothesized that CNL targets STAT3, a critical regulator of hematopoietic biology. We observed that CNL treatment reduced phosphorylated STAT3 at both Y705 and S727 residues in CLL cell lines and patient cells. This, in turn, reduced STAT3 transcriptional activity and expression of critical STAT3-dependent survival factors like Mcl-1 and survivin. The effect of CNL on STAT3 was further confirmed ex vivo as shown by reduced STAT3 phosphorylation in xenograft tumors obtained from mice treated with CNL. CNL suppressed STAT3 phosphorylation at Y705 and S727 through reduction in BTK activity and MEK1/2 kinase/PKC activities, respectively. Moreover, a synergistic reduction in CLL cell viability was observed on co-treatment with CNL and the BTK inhibitor, ibrutinib. Expression of an oncogenic form of STAT3 conferred partial resistance to CNL, providing confirmation that STAT3 mediates CNL-induced cell death. Taken together, these findings provide the first body of evidence demonstrating ceramide regulation of STAT3 phosphorylation. These results are also the first to demonstrate an effect of ceramide on BTK, a critical kinase mediating the B-cell receptor signaling in CLL cells and suggest a novel and synergistic combination of CNL and BTK inhibitors for CLL treatment.
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- 2017
7. Blimp-1 impairs T cell function via upregulation of TIGIT and PD-1 in patients with acute myeloid leukemia
- Author
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Witold B. Rybka, Hui Zeng, Liuluan Zhu, Ming Wang, Raymond J. Hohl, Neil Palmisiano, Bei Jia, Jianhong Zhang, Michael G. Bayerl, W. Christopher Ehmann, Todd D. Schell, Yaxian Kong, Hong Zheng, and David F. Claxton
- Subjects
Adult ,Male ,Transcriptional Activation ,0301 basic medicine ,Cancer Research ,TIGIT ,T-Lymphocytes ,medicine.medical_treatment ,T cell ,Programmed Cell Death 1 Receptor ,lcsh:RC254-282 ,Flow cytometry ,Young Adult ,03 medical and health sciences ,Immune system ,PD-1 ,Acute myeloid leukemia (AML) ,medicine ,Humans ,Receptors, Immunologic ,Molecular Biology ,Transcription factor ,Aged ,T cell exhaustion ,medicine.diagnostic_test ,Gene Expression Regulation, Leukemic ,lcsh:RC633-647.5 ,Chemistry ,Research ,Myeloid leukemia ,lcsh:Diseases of the blood and blood-forming organs ,Hematology ,Middle Aged ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,medicine.disease ,Blimp-1 ,Up-Regulation ,Leukemia, Myeloid, Acute ,Leukemia ,030104 developmental biology ,Cytokine ,medicine.anatomical_structure ,Oncology ,Cancer research ,Cytokines ,Female ,Positive Regulatory Domain I-Binding Factor 1 - Abstract
Background T cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif (ITIM) domain (TIGIT) and programmed cell death protein 1 (PD-1) are important inhibitory receptors that associate with T cell exhaustion in acute myeloid leukemia (AML). In this study, we aimed to determine the underlying transcriptional mechanisms regulating these inhibitory pathways. Specifically, we investigated the role of transcription factor B lymphocyte-induced maturation protein 1 (Blimp-1) in T cell response and transcriptional regulation of TIGIT and PD-1 in AML. Methods Peripheral blood samples collected from patients with AML were used in this study. Blimp-1 expression was examined by flow cytometry. The correlation of Blimp-1 expression to clinical characteristics of AML patients was analyzed. Phenotypic and functional studies of Blimp-1-expressing T cells were performed using flow cytometry-based assays. Luciferase reporter assays and ChIP assays were applied to assess direct binding and transcription activity of Blimp-1. Using siRNA to silence Blimp-1, we further elucidated the regulatory role of Blimp-1 in the TIGIT and PD-1 expression and T cell immune response. Results Blimp-1 expression is elevated in T cells from AML patients. Consistent with exhaustion, Blimp-1+ T cells upregulate multiple inhibitory receptors including PD-1 and TIGIT. In addition, they are functionally impaired manifested by low cytokine production and decreased cytotoxicity capacity. Importantly, the functional defect is reversed by inhibition of Blimp-1 via siRNA knockdown. Furthermore, Blimp-1 binds to the promoters of PD-1 and TIGIT and positively regulates their expression. Conclusions Our study demonstrates an important inhibitory effect of Blimp-1 on T cell response in AML; thus, targeting Blimp-1 and its regulated molecules to improve the immune response may provide effective leukemia therapeutics. Electronic supplementary material The online version of this article (doi:10.1186/s13045-017-0486-z) contains supplementary material, which is available to authorized users.
- Published
- 2017
8. Oral administration of analgesia and anxiolysis for pain associated with bone marrow biopsy
- Author
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Michael G. Bayerl, Giampaolo Talamo, Jason Liao, David F. Claxton, and Maurizio Zangari
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Adult ,Male ,Scarce data ,medicine.medical_specialty ,Pain medicine ,Administration, Oral ,Pain ,Lorazepam ,Bone Marrow ,Oral administration ,Biopsy ,medicine ,Humans ,Acetaminophen ,Aged ,Pain Measurement ,Aged, 80 and over ,Analgesics ,Pain score ,medicine.diagnostic_test ,business.industry ,Biopsy, Needle ,Middle Aged ,Surgery ,Clinical trial ,medicine.anatomical_structure ,Anti-Anxiety Agents ,Oncology ,Anesthesia ,Female ,Bone marrow ,business ,Oxycodone ,Anesthesia, Local - Abstract
Medical literature provides only scarce data about the degree of pain experienced by patients undergoing a bone marrow aspiration and biopsy (BMAB), and little is known about the factors that can modify the perception of pain. In this study, we evaluated the effectiveness of a combination of analgesia and anxiolysis in reducing the pain score of patients undergoing BMAB.Eighty-four consecutive adult patients underwent BMAB after local anesthesia with 5 mL of lidocaine hydrochloride 1% aqueous solution in the left posterior superior iliac crest. Analgesia was obtained with acetaminophen 650 mg and oxycodone 10 mg, and anxiolysis was obtained with lorazepam 2 mg, all drugs given once orally 30 min before the procedure. We assessed the pain level with the Wong-Baker Faces Pain Rating Scale, which distinguishes six levels of pain, from 0 to 5.The 34 patients who received an oral administration of analgesia and anxiolysis reported pain at lower levels, i.e., in the range of 0-2, more frequently than the 50 patients who underwent BMAB without analgesia/anxiolysis (78% vs 64%, respectively). Among several predictors analyzed using a multivariate regression model, three were found to be associated with decreased pain level: the use of analgesia/anxiolysis, male sex, and increase in age (all with p values0.05). Length of the extracted bone specimen, body mass index, and need of a spinal needle for anesthesia in obese patients did not predict for pain level.An oral administration of prophylactic regimen of analgesia and anxiolysis, at the above-mentioned doses, produced a statistically significant reduction of the perception of pain in patients undergoing BMAB, but its effect did not seem to provide a major and clinically significant reduction of pain level.
- Published
- 2009
9. BU and CY as conditioning regimen for autologous transplant in patients with multiple myeloma
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D W Dougherty, David F. Claxton, Witold B. Rybka, Jeffrey Sivik, Christopher Ehmann, Joseph J. Drabick, and Giampaolo Talamo
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Adult ,Oncology ,medicine.medical_specialty ,Transplantation Conditioning ,Cyclophosphamide ,medicine.medical_treatment ,Transplantation, Autologous ,chemistry.chemical_compound ,immune system diseases ,hemic and lymphatic diseases ,Internal medicine ,Immunopathology ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Humans ,Autologous transplantation ,Busulfan ,Multiple myeloma ,Aged ,Retrospective Studies ,Transplantation ,Chemotherapy ,business.industry ,Hematopoietic Stem Cell Transplantation ,Hematology ,Middle Aged ,medicine.disease ,Combined Modality Therapy ,Nitrogen mustard ,Surgery ,Survival Rate ,surgical procedures, operative ,chemistry ,Stem cell ,Multiple Myeloma ,business ,medicine.drug - Abstract
High-dose melphalan is considered the current standard of care among the preparative regimens used in peripheral blood autologous SCT (ASCT) for multiple myeloma (MM). We report the results of a single ASCT in 79 MM patients using the BU/CY conditioning regimen, with BU 1 mg/kg p.o. or 0.8 mg/kg i.v. every 6 h x 16 doses, and CY 60 mg/kg per day i.v. for 2 days. ASCT was carried out in first (62%) or subsequent remission/refractory disease (38%). For an overall RR of 86%, 48 and 20 patients achieved PR and CR, respectively. At a median follow-up of 41 months (range 2-132 months), the estimated median OS and PFS were 45 months (95% confidence interval (CI)=38-92) and 20 months (95% CI=15-25), respectively. The BU/CY regimen was well tolerated, and transplant-related mortality was 4%. Clinical outcomes of the BU/CY regimen are not superior to those obtained in historical controls with high-dose melphalan followed by a single ASCT. Therefore, considering even the greater complexity of administration of the BU/CY regimen compared with that of single-agent melphalan, we believe the latter should remain the conditioning regimen of choice for ASCT in MM.
- Published
- 2009
10. Prognostic factors for disease progression after high-dose chemotherapy and autologous hematopoietic stem cell transplantation for recurrent or refractory Hodgkin's lymphoma
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Borje S. Andersson, J. Cox, Fernando Cabanillas, Paolo Anderlini, Fredrick B. Hagemeister, Chitra Hosing, K. Van Besien, Sergio Giralt, Donna Przepiorka, Richard E. Champlin, Uday R. Popat, David F. Claxton, J. Romaguera, Issa F. Khouri, James Gajewski, Chul S. Ha, Rima M. Saliba, and Maria Alma Rodriguez
- Subjects
Adult ,Male ,Oncology ,medicine.medical_specialty ,Time Factors ,medicine.medical_treatment ,Graft vs Host Disease ,Hematopoietic stem cell transplantation ,Disease-Free Survival ,Autologous stem-cell transplantation ,Recurrence ,Risk Factors ,Internal medicine ,medicine ,Humans ,Transplantation, Homologous ,Autologous transplantation ,Transplantation ,Chemotherapy ,business.industry ,Hematopoietic Stem Cell Transplantation ,Induction chemotherapy ,Hematology ,Middle Aged ,Prognosis ,Hodgkin's lymphoma ,medicine.disease ,Hodgkin Disease ,Chemotherapy regimen ,Surgery ,Treatment Outcome ,Acute Disease ,Multivariate Analysis ,Disease Progression ,Female ,business - Abstract
Our purpose was to study the risk factors associated with disease progression after high-dose chemotherapy followed by autologous stem cell transplantation in patients with recurrent or refractory Hodgkin's lymphoma (HL). We analyzed the long-term outcome of 184 patients with recurrent or refractory HL who underwent autologous hematopoietic stem cell transplantation. At the time of transplantation, 82 patients were in first relapse or second remission, 46 patients were refractory to the primary induction chemotherapy, and 56 patients were beyond first relapse or second remission. In 64 patients, the disease had proved refractory to the chemotherapy regimen administered immediately prior to transplantation. The median follow-up of patients who were alive and free of disease at the time of this report was 8.9 years (range, 0.1-19.0 years). At 10 years, the overall and disease-free survival rates were 34% (95% CI 27-42) and 29% (95% CI 22-36) respectively. The major cause of treatment failure was disease relapse. Chemotherapy resistance prior to transplantation, advanced stage, and higher number of chemotherapy regimens administered prior to transplantation were adverse prognostic factors for disease progression. We conclude that autologous transplantation is an effective salvage treatment for recurrent HL.
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- 2004
11. Decitabine with allogeneic peripheral blood stem cell transplantation in the therapy of leukemia relapse following a prior transplant: results of a phase I study
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Sergio Giralt, Susan O'Brien, Paolo Anderlini, M. Davis, Naoto T. Ueno, Borje S. Andersson, James Gajewski, Farhad Ravandi, Hagop M. Kantarjian, M. Korbling, David F. Claxton, M. Donato, A. Cohen, Issa F. Khouri, D. DeVos, and Richard E. Champlin
- Subjects
Adult ,Oncology ,Antimetabolites, Antineoplastic ,medicine.medical_specialty ,medicine.medical_treatment ,Decitabine ,Hematopoietic stem cell transplantation ,Cohort Studies ,Recurrence ,Internal medicine ,Acute lymphocytic leukemia ,medicine ,Humans ,Transplantation, Homologous ,Transplantation ,Chemotherapy ,Acute leukemia ,Leukemia ,Dose-Response Relationship, Drug ,business.industry ,Remission Induction ,Hematopoietic Stem Cell Transplantation ,Hematology ,Middle Aged ,medicine.disease ,Survival Analysis ,Surgery ,Treatment Outcome ,Azacitidine ,business ,Follow-Up Studies ,medicine.drug ,Chronic myelogenous leukemia - Abstract
Relapse after allogeneic progenitor cell transplant is associated with a poor prognosis for patients with advanced leukemia, with few curative options available. Use of novel chemotherapeutic agents with limited toxicity is warranted. We investigated the role of decitabine, a pyrimidine analogue with significant anti-leukemic effect and limited toxicity, in this setting. Fourteen patients with advanced acute leukemia or transformed chronic myelogenous leukemia (CML) who had failed previous allogeneic transplant were treated. Decitabine at doses of 100 mg/m2 to 150 mg/m2 given every 12 h for 5 days was followed by infusion of stem cells from the original donor 2 to 5 days after the completion of chemotherapy. Dose of decitabine was escalated in cohorts of three patients based on the modified Fibonacci scheme. The primary study end-point was assessment of the toxicity of the regimen with secondary endpoints of response and survival. Eight patients responded with either a complete remission or partial hematological remission (absence of blasts in peripheral blood and bone marrow but with platelet count
- Published
- 2001
12. Thiotepa, busulfan, cyclophosphamide (TBC) and autologous hematopoietic transplantation: an intensive regimen for the treatment of multiple myeloma
- Author
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Naoto T. Ueno, P. Anderlini, Donna M. Weber, Ana Aleman, Richard E. Champlin, Borje S. Andersson, M. Donato, Meletios A. Dimopoulos, Terry L. Smith, David F. Claxton, M. Korbling, Issa F. Khouri, Avichai Shimoni, Sergio Giralt, and Raymond Alexanian
- Subjects
Adult ,Male ,Oncology ,medicine.medical_specialty ,Time Factors ,Transplantation Conditioning ,medicine.medical_treatment ,ThioTEPA ,Transplantation, Autologous ,Refractory ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Humans ,Autologous transplantation ,Busulfan ,Cyclophosphamide ,Multiple myeloma ,Aged ,Transplantation ,Chemotherapy ,business.industry ,Graft Survival ,Remission Induction ,Hematopoietic Stem Cell Transplantation ,Hematology ,Middle Aged ,Prognosis ,medicine.disease ,Survival Analysis ,Surgery ,Regimen ,Female ,Multiple Myeloma ,business ,Thiotepa ,medicine.drug - Abstract
The study was designed to evaluate the efficacy and safety of an intensive, tri-alkylator conditioning regimen, consisting of thiotepa, busulfan and cyclophosphamide (TBC), prior to autologous hematopoietic cell transplantation in patients with multiple myeloma (MM) and to analyze factors associated with outcome. One hundred and twenty patients with MM received high-dose chemotherapy with TBC followed by autologous bone marrow (n = 24) or peripheral blood stem cell (PBSC) transplantation (n = 96). Fifty-four patients had chemosensitive disease and 66 had refractory disease at the time of transplantation. The overall response rate was 81% and the complete remission (CR) rate was 26%. Patients with chemosensitive disease had a CR rate of 52% vs 5% for patients with refractory disease. Multivariable analysis determined disease status at transplant as the factor most likely associated with long survival. Estimated median survival was 48, 35 and 9 months for patients with chemosensitive, primary refractory or disease in refractory relapse, respectively. Short interval from diagnosis to transplant among patients with primary refractory disease and younger age were also favorable prognostic factors for survival. Patients with refractory disease pre-transplant who achieved remission criteria rapidly after treatment had a worse outcome than the slow responders. Treatment-related mortality with the introduction of PBSC and better supportive care was 4.8%. In conclusion, TBC is an effective and relatively well-tolerated intensive conditioning regimen in patients with MM. A more favorable outcome was observed in patients with chemosensitive disease and with early treatment for primary refractory disease. TBC merits further study in these subgroups and comparison with alternative regimens in prospective studies is warranted.
- Published
- 2001
13. CBFβ-SMMHC, expressed in M4Eo AML, reduced CBF DNA-binding and inhibited the G1 to S cell cycle transition at the restriction point in myeloid and lymphoid cells
- Author
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Wangsen Cao, Christine A. Kelley, Nancy A. Speck, Martin Britos-Bray, Alan D. Friedman, David F. Claxton, and Pengfei Liu
- Subjects
Cancer Research ,Cell type ,Myeloid ,Lymphoma ,Recombinant Fusion Proteins ,Cellular differentiation ,Blotting, Western ,Endogeny ,Myosins ,Biology ,Retinoblastoma Protein ,Leukemia, Myelomonocytic, Acute ,S Phase ,Mice ,Granulocyte Colony-Stimulating Factor ,Genetics ,medicine ,Animals ,Fluorescent Antibody Technique, Indirect ,Molecular Biology ,Peroxidase ,G1 Phase ,Cell Differentiation ,Cell cycle ,Molecular biology ,Receptors, Interleukin-3 ,DNA-Binding Proteins ,Zinc ,Haematopoiesis ,medicine.anatomical_structure ,Transcription Factor AP-2 ,Cell culture ,Apoptosis ,Cancer research ,Metallothionein ,Transcription Factors ,circulatory and respiratory physiology - Abstract
CBF beta-SMMHC is expressed from the inv(16) chromosome in M4Eo AML. Mice lacking CBF subunits or expressing the CBF beta-SMMHC or AML1-ETO oncoproteins failed to develop definitive hematopoiesis. To investigate these effects on hematopoiesis, we expressed CBF beta-SMMHC from the metallothionein promoter, in both 32D cl3 myeloid cells and Ba/F3 B-lymphoid cells. Addition of zinc increased CBF beta-SMMHC levels more than tenfold, with higher levels evident in Ba/F3 lines. Levels obtained in 32D cl3 cells were similar to those of endogenous CBF beta. Indirect immunofluorescence revealed zinc-inducible speckled, nuclear staining in Ba/F3 cells and diffuse nuclear staining in 32D cl3 cells. CBF beta-SMMHC reduced endogenous CBF DNA-binding fivefold in both cell types, increased cell generation time 1.9-fold, on average, in 32D cl3 cells and 1.5-fold in Ba/ F3 cells and decreased tritiated thymidine incorporation into DNA correspondingly. CBF beta-SMMHC increased the proportion of cells in G1 1.7-fold, on average, in 32D cl3 and Ba/F3 cells, and decreased the proportion of cells in S phase by a similar degree. CBF beta-SMMHC induced a marked increase in hypophosphorylated Rb, but did not alter IL-3 Receptor alpha or beta subunit levels. Neither apoptosis nor 32D differentiation was induced by zinc in IL-3 in these lines. Induction of CBF beta-SMMHC in 32D cl3 cells did not inhibit their differentiation to neutrophils or their expression of myeloperoxidase mRNA in G-CSF, and did not produce an eosinophilic phenotype. Additional, proliferative genetic changes in M4eo AMLs might potentiate inhibition of differentiation by CBF beta-SMMHC by allowing its increased expression.
- Published
- 1997
14. Atg5-dependent autophagy contributes to the development of acute myeloid leukemia in an MLL-AF9-driven mouse model
- Author
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Jennifer M. Atkinson, Qiang Liu, Hong Gang Wang, Longgui Chen, and David F. Claxton
- Subjects
0301 basic medicine ,Cancer Research ,Myeloid ,Oncogene Proteins, Fusion ,Immunology ,ATG5 ,Bone Marrow Cells ,Biology ,Autophagy-Related Protein 5 ,Mice ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,hemic and lymphatic diseases ,Autophagy ,medicine ,Animals ,Humans ,neoplasms ,Bone Marrow Transplantation ,Gene Expression Regulation, Leukemic ,Myeloid leukemia ,Cell Biology ,medicine.disease ,Survival Analysis ,Mice, Inbred C57BL ,Transplantation ,Disease Models, Animal ,Leukemia, Myeloid, Acute ,Leukemia ,Cell Transformation, Neoplastic ,030104 developmental biology ,medicine.anatomical_structure ,Neoplastic Stem Cells ,Cancer research ,Original Article ,Bone marrow ,Stem cell ,Lysosomes ,Gene Deletion ,Signal Transduction - Abstract
Acute myeloid leukemia (AML) is a hierarchical hematopoietic malignancy originating from leukemic stem cells (LSCs). Autophagy is a lysosomal degradation pathway that is hypothesized to be important for the maintenance of AML as well as contribute to chemotherapy response. Here we employ a mouse model of AML expressing the fusion oncogene MLL-AF9 and explore the effects of Atg5 deletion, a key autophagy protein, on the malignant transformation and progression of AML. Consistent with a transient decrease in colony-forming potential in vitro, the in vivo deletion of Atg5 in MLL-AF9-transduced bone marrow cells during primary transplantation prolonged the survival of recipient mice, suggesting that autophagy has a role in MLL-AF9-driven leukemia initiation. In contrast, deletion of Atg5 in malignant AML cells during secondary transplantation did not influence the survival or chemotherapeutic response of leukemic mice. Interestingly, autophagy was found to be involved in the survival of differentiated myeloid cells originating from MLL-AF9-driven LSCs. Taken together, our data suggest that Atg5-dependent autophagy may contribute to the development but not chemotherapy sensitivity of murine AML induced by MLL-AF9.
- Published
- 2016
15. PD-1hiTIM-3+ T cells associate with and predict leukemia relapse in AML patients post allogeneic stem cell transplantation
- Author
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David F. Claxton, Yaxian Kong, Witold B. Rybka, Liuluan Zhu, W. C. Ehmann, Jianhong Zhang, Hui Zeng, Todd D. Schell, and Hong Zheng
- Subjects
Male ,Interleukin 2 ,Myeloid ,T-Lymphocytes ,medicine.medical_treatment ,Programmed Cell Death 1 Receptor ,Hematopoietic stem cell transplantation ,Disease-Free Survival ,Biomarkers, Tumor ,medicine ,Humans ,Transplantation, Homologous ,Hepatitis A Virus Cellular Receptor 2 ,Aged ,business.industry ,Hematopoietic Stem Cell Transplantation ,Membrane Proteins ,Myeloid leukemia ,Hematology ,Middle Aged ,medicine.disease ,Transplantation ,Leukemia, Myeloid, Acute ,Leukemia ,Treatment Outcome ,medicine.anatomical_structure ,Oncology ,Immunology ,Cytokines ,Original Article ,Female ,Tumor necrosis factor alpha ,Neoplasm Recurrence, Local ,Stem cell ,business ,medicine.drug - Abstract
Prognosis of leukemia relapse post allogeneic stem cell transplantation (alloSCT) is poor and effective new treatments are urgently needed. T cells are pivotal in eradicating leukemia through a graft versus leukemia (GVL) effect and leukemia relapse is considered a failure of GVL. T-cell exhaustion is a state of T-cell dysfunction mediated by inhibitory molecules including programmed cell death protein 1 (PD-1) and T-cell immunoglobulin domain and mucin domain 3 (TIM-3). To evaluate whether T-cell exhaustion and inhibitory pathways are involved in leukemia relapse post alloSCT, we performed phenotypic and functional studies on T cells from peripheral blood of acute myeloid leukemia patients receiving alloSCT. Here we report that PD-1hiTIM-3+ cells are strongly associated with leukemia relapse post transplantation. Consistent with exhaustion, PD-1hiTIM-3+ T cells are functionally deficient manifested by reduced production of interleukin 2 (IL-2), tumor necrosis factor-α (TNF-α) and interferon-γ (IFN-γ). In addition, these cells demonstrate a phenotype consistent with exhausted antigen-experienced T cells by losing TN and TEMRA subsets. Importantly, increase of PD-1hiTIM-3+ cells occurs before clinical diagnosis of leukemia relapse, suggesting their predictive value. Results of our study provide an early diagnostic approach and a therapeutic target for leukemia relapse post transplantation.
- Published
- 2015
16. Clofarabine and CY do not yield reliable engraftment of hematopoietic stem cells
- Author
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Junjia Zhu, David F. Claxton, J Karch, and W C Ehmann
- Subjects
Transplantation ,Haematopoiesis ,business.industry ,Yield (chemistry) ,medicine ,Cancer research ,Clofarabine ,Hematology ,Stem cell ,business ,Virology ,medicine.drug - Published
- 2011
17. Potential for therapy with AML-derived dendritic cells
- Author
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David F. Claxton and Aniruddha Choudhury
- Subjects
Cancer Research ,Pathology ,medicine.medical_specialty ,Follicular dendritic cells ,business.industry ,medicine.medical_treatment ,Dendritic Cells ,Hematology ,Dendritic cell ,Immunotherapy ,Immunotherapy, Adoptive ,Cell therapy ,Leukemia, Myeloid, Acute ,Oncology ,Humans ,Medicine ,business ,Antigen-presenting cell - Published
- 2001
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