80 results on '"Keating, Michael J."'
Search Results
2. Leukemia research, 2008.
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Freireich EJ, Kantarjian H, and Keating MJ
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- Humans, Medical Oncology trends, Leukemia diagnosis, Leukemia therapy, Medical Oncology methods
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- 2009
- Full Text
- View/download PDF
3. Analysis of human leukaemias and lymphomas using extensive immunophenotypes from an antibody microarray.
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Belov L, Mulligan SP, Barber N, Woolfson A, Scott M, Stoner K, Chrisp JS, Sewell WA, Bradstock KF, Bendall L, Pascovici DS, Thomas M, Erber W, Huang P, Sartor M, Young GA, Wiley JS, Juneja S, Wierda WG, Green AR, Keating MJ, and Christopherson RI
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- Acute Disease, Antigens, CD blood, Antigens, Neoplasm blood, Bone Marrow immunology, Diagnosis, Differential, Flow Cytometry, Humans, Immunophenotyping methods, Leukemia classification, Leukemia diagnosis, Leukemia, Lymphocytic, Chronic, B-Cell diagnosis, Leukemia, Lymphocytic, Chronic, B-Cell immunology, Lymphoma classification, Lymphoma diagnosis, Lymphoma, B-Cell classification, Lymphoma, B-Cell diagnosis, Lymphoma, B-Cell immunology, Protein Array Analysis methods, Leukemia immunology, Lymphoma immunology
- Abstract
A novel antibody microarray has been developed that provides an extensive immunophenotype of leukaemia cells. The assay is a solid phase cell-capture technique in which 82 antigens are studied simultaneously. This paper presents the analysis of 733 patients with a variety of leukaemias and lymphomas from peripheral blood and bone marrow. Discriminant Function Analysis of the expression profiles from these 733 patients and 63 normal subjects were clustered and showed high levels of consistency with diagnoses obtained using conventional clinical and laboratory criteria. The overall levels of consensus for classification using the microarray compared with established criteria were 93.9% (495/527 patients) for peripheral blood and 97.6% (201/206 patients) for bone marrow aspirates, showing that the extensive phenotype alone was frequently able to classify the disease when the leukaemic clone was the dominant cell population present. Immunophenotypes for neoplastic cells were distinguishable from normal cells when the leukaemic cell count was at least 5 x 10(9) cells/l in peripheral blood, or 20% of cells obtained from bone marrow aspirates. This technique may be a useful adjunct to flow cytometry and other methods when an extensive phenotype of the leukaemia cell is desired for clinical trials, research and prognostic factor analysis.
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- 2006
- Full Text
- View/download PDF
4. Pharmacokinetics and pharmacodynamics of plasma clofarabine and cellular clofarabine triphosphate in patients with acute leukemias.
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Gandhi V, Kantarjian H, Faderl S, Bonate P, Du M, Ayres M, Rios MB, Keating MJ, and Plunkett W
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- Adenine Nucleotides, Antineoplastic Agents pharmacokinetics, Antineoplastic Agents pharmacology, Clofarabine, DNA metabolism, Dose-Response Relationship, Drug, Humans, Leukemia, Myeloid, Acute drug therapy, Maximum Tolerated Dose, Models, Chemical, Neoplastic Cells, Circulating, Oligonucleotides chemistry, Precursor Cell Lymphoblastic Leukemia-Lymphoma drug therapy, Time Factors, Arabinonucleosides pharmacokinetics, Arabinonucleosides pharmacology, Leukemia drug therapy
- Abstract
Purpose: The purpose of our study was to investigate the pharmacology of clofarabine and its triphosphate and the pharmacodynamic actions in circulating blasts obtained from acute leukemia patients who entered a Phase I clinical trial of clofarabine., Experimental Design: Adults with refractory acute leukemias including lymphoblastic (ALL), myelogenous (AML) and chronic myelogenous leukemia in blastic phase (CML-BP) received clofarabine from 4 mg/m(2) to 55 mg/m2/day for 5 days as a 1-h i.v. infusion. A total of 26 of the 32 patients were studied for pharmacological investigations., Results: The maximum tolerated dose was 40 mg/m2/day for 5 days. Plasma pharmacology studies done in 25 patients indicate a linear increase in the plasma clofarabine concentration with increasing doses. At 40 mg/m2 the median plasma clofarabine level was 1.5 micro M (range, 0.42-3.2 micro M; n = 7). Cellular pharmacokinetic studies done at the end of the first clofarabine infusion in 26 patients appeared dose proportional but showed a wide variation in the concentrations of clofarabine triphosphate. At the maximum tolerated dose, the concentration was a median 19 micro M (range, 3-52 micro M). In the majority of cases, more than 50% of the analog triphosphate was present at 24 h after infusion. Compared with clofarabine triphosphate concentration, the endogenous level of dATP was low, resulting in a favorable ratio of analog triphosphate:normal deoxynucleoside triphosphate (dNTP) for incorporation into DNA. In association with the accumulation of triphosphate, there was a decrease in DNA synthesis. At 40- and 55-mg/m2 doses, the inhibition of DNA synthesis was maintained to 24 h., Conclusions: Clofarabine at the maximum tolerated dose was effective with regard to inhibition of DNA synthesis and decline in circulating leukemia blasts. Given the clinical activity of clofarabine in adult acute leukemias, it is of interest to conduct a detailed characterization of the cellular pharmacology of clofarabine triphosphate and its relationship to clinical responses.
- Published
- 2003
5. Phase II study of alemtuzumab in chronic lymphoproliferative disorders.
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Ferrajoli A, O'Brien SM, Cortes JE, Giles FJ, Thomas DA, Faderl S, Kurzrock R, Lerner S, Kontoyiannis DP, and Keating MJ
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- Adult, Aged, Aged, 80 and over, Alemtuzumab, Antibodies, Monoclonal adverse effects, Antibodies, Monoclonal, Humanized, Antibodies, Neoplasm adverse effects, Antineoplastic Agents adverse effects, Humans, Immunocompromised Host, Infections immunology, Leukemia immunology, Leukemia mortality, Leukemia, Lymphocytic, Chronic, B-Cell drug therapy, Leukemia, Prolymphocytic drug therapy, Lymphoma immunology, Lymphoma mortality, Middle Aged, Survival Rate, Antibodies, Monoclonal therapeutic use, Antibodies, Neoplasm therapeutic use, Antineoplastic Agents therapeutic use, Leukemia drug therapy, Lymphoma drug therapy
- Abstract
Background: Pilot studies showed that alemtuzumab is active in lymphoproliferative disorders. The authors conducted a Phase II trial to evaluate the efficacy and safety of alemtuzumab in advanced or refractory chronic lymphoproliferative disorders., Methods: Seventy-eight patients were enrolled. The most common diagnoses were chronic lymphocytic leukemia (n = 42 patients) and T-cell prolymphocytic leukemia (n = 18 patients). Before entering the study, the patients had received multiple therapies (median, three therapies) and the median time from diagnosis was 7 years. Alemtuzumab was given intravenously at doses of 3 mg, 10 mg, and 30 mg on 3 consecutive days, after which 30 mg was administered 3 times a week. Patients were treated for 4-12 weeks depending on disease response. All patients received prophylactic trimethoprim/sulfamethoxazole and valacyclovir., Results: The overall response rate was 35%, the complete response (CR) rate was 13%, and the partial response (PR) rate was 22%. The median duration of response was 18 months for patients achieving a CR and 7 months for patients achieving a PR. The median duration of survival was 25 months for patients who had a response and 12 months for the entire population. Normalization of the lymphocyte count was observed in 84% of patients and resolution of bone marrow involvement was observed in 49% of patients. The most common infusion-related adverse events were fever, rigors, skin rash, nausea, and dyspnea. These were most common during the first week of therapy. Hematologic toxicity was comprised of long-lasting lymphocytopenia and transient neutropenia and thrombocytopenia. Thirty-six patients (46%) experienced at least one episode of fever or infection., Conclusions: Alemtuzumab has a high response rate in patients with chronic lymphoproliferative disorders., (Copyright 2003 American Cancer Society.DOI 10.1002/cncr.11551)
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- 2003
- Full Text
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6. Growth dynamics in naturally progressing chronic lymphocytic leukaemia
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Gruber, Michaela, Bozic, Ivana, Leshchiner, Ignaty, Livitz, Dimitri, Stevenson, Kristen, Rassenti, Laura, Rosebrock, Daniel, Taylor-Weiner, Amaro, Olive, Oriol, Goyetche, Reaha, Fernandes, Stacey M, Sun, Jing, Stewart, Chip, Wong, Alicia, Cibulskis, Carrie, Zhang, Wandi, Reiter, Johannes G, Gerold, Jeffrey M, Gribben, John G, Rai, Kanti R, Keating, Michael J, Brown, Jennifer R, Neuberg, Donna, Kipps, Thomas J, Nowak, Martin A, Getz, Gad, and Wu, Catherine J
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Biological Sciences ,Biomedical and Clinical Sciences ,Cardiovascular Medicine and Haematology ,Oncology and Carcinogenesis ,Clinical Research ,Rare Diseases ,Hematology ,Cancer ,Genetics ,Lymphoma ,Human Genome ,2.1 Biological and endogenous factors ,Aetiology ,Cell Proliferation ,Clone Cells ,Cohort Studies ,Disease Progression ,Evolution ,Molecular ,Female ,High-Throughput Nucleotide Sequencing ,Humans ,Leukemia ,Lymphocytic ,Chronic ,B-Cell ,Male ,Neoplasm Recurrence ,Local ,Recurrence ,Reproducibility of Results ,General Science & Technology - Abstract
How the genomic features of a patient's cancer relate to individual disease kinetics remains poorly understood. Here we used the indolent growth dynamics of chronic lymphocytic leukaemia (CLL) to analyse the growth rates and corresponding genomic patterns of leukaemia cells from 107 patients with CLL, spanning decades-long disease courses. We found that CLL commonly demonstrates not only exponential expansion but also logistic growth, which is sigmoidal and reaches a certain steady-state level. Each growth pattern was associated with marked differences in genetic composition, the pace of disease progression and the extent of clonal evolution. In a subset of patients, whose serial samples underwent next-generation sequencing, we found that dynamic changes in the disease course of CLL were shaped by the genetic events that were already present in the early slow-growing stages. Finally, by analysing the growth rates of subclones compared with their parental clones, we quantified the growth advantage conferred by putative CLL drivers in vivo.
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- 2019
7. Efficacy and predictors of response of lenalidomide and rituximab in patients with treatment-naive and relapsed CLL
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Strati, Paolo, Takahashi, Koichi, Peterson, Christine B, Keating, Michael J, Thompson, Philip A, Daver, Naval G, Jain, Nitin, Burger, Jan A, Estrov, Zeev, O'Brien, Susan M, Kantarjian, Hagop M, Wierda, William G, Futreal, P Andrew, and Ferrajoli, Alessandra
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Biomedical and Clinical Sciences ,Cardiovascular Medicine and Haematology ,Rare Diseases ,Clinical Research ,Hematology ,Lymphoma ,Cancer ,Adult ,Aged ,Drug Administration Schedule ,Female ,Humans ,Immunologic Factors ,Kaplan-Meier Estimate ,Lenalidomide ,Leukemia ,Lymphocytic ,Chronic ,B-Cell ,Male ,Middle Aged ,Multivariate Analysis ,Neutropenia ,Progression-Free Survival ,Receptors ,Notch ,Recurrence ,Rituximab ,Treatment Outcome ,Cardiovascular medicine and haematology - Abstract
This phase 2 study was conducted to prospectively evaluate how clinical and biological factors correlate with outcome in patients with treatment-naive (TN) and relapsed (R) chronic lymphocytic leukemia (CLL) treated with lenalidomide and rituximab. Oral lenalidomide 10 mg was administered daily starting on day 9 of cycle 1. IV rituximab 375 mg/m2 was administered weekly during cycle 1 and every 4 weeks for cycles 3 to 12. Sequencing of a custom panel of 295 genes was performed in pretreatment bone marrow samples. The study included 61 patients with TN CLL and 59 with R CLL; the overall response rate (ORR) was 73% and 64%, respectively. A baseline β2-microglobulin level 2 previous therapies (P = .02) was the only factor associated with shorter PFS in R patients. A trend for association between mutations in the NOTCH pathway and shorter PFS was observed in TN CLL (P = .15). Further exploration of the NOTCH pathway may help optimize the efficacy of this combination in patients with CLL. This study protocol was approved by the University of Texas MD Anderson Cancer Center institutional review board and registered at clinicaltrials.gov (#NCT01446133).
- Published
- 2019
8. Serial minimal residual disease (MRD) monitoring during first-line FCR treatment for CLL may direct individualized therapeutic strategies
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Thompson, Philip A, Peterson, Christine B, Strati, Paolo, Jorgensen, Jeff, Keating, Michael J, O’Brien, Susan M, Ferrajoli, Alessandra, Burger, Jan A, Estrov, Zeev, Jain, Nitin, Kadia, Tapan M, Borthakur, Gautam, DiNardo, Courtney D, Daver, Naval, Jabbour, Elias, and Wierda, William G
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Biomedical and Clinical Sciences ,Cardiovascular Medicine and Haematology ,Oncology and Carcinogenesis ,Rare Diseases ,Clinical Research ,Prevention ,4.2 Evaluation of markers and technologies ,Detection ,screening and diagnosis ,Good Health and Well Being ,Adult ,Aged ,Aged ,80 and over ,Antineoplastic Combined Chemotherapy Protocols ,Bone Marrow ,Cyclophosphamide ,Disease-Free Survival ,Female ,Humans ,Immunotherapy ,Leukemia ,Lymphocytic ,Chronic ,B-Cell ,Male ,Middle Aged ,Neoplasm ,Residual ,Prospective Studies ,Rituximab ,Vidarabine ,Clinical Sciences ,Immunology ,Cardiovascular medicine and haematology ,Clinical sciences ,Oncology and carcinogenesis - Abstract
Achieving undetectable MRD (U-MRD) status after chemoimmunotherapy predicts longer progression-free and overall survival. The predictive factors and timing of relapse in patients with U-MRD and value of interim MRD analysis are ill-defined. This was a prospective study of 289 patients with CLL treated first-line with FCR. MRD analysis was performed after course 3 (C3) and at end of therapy (EOT) in bone marrow using 4-color flow cytometry (sensitivity 10-4). Eighteen percent of patients had U-MRD after C3 and 48% at EOT. U-MRD status at EOT was associated with longer PFS (median NR vs 38 mo, p 1%) after C3 predicted greater likelihood of U-MRD status at EOT (64% vs 9%, p 1% after C3 (median 73 mo vs 41 mo, p
- Published
- 2018
9. Dynamic changes in CCL3 and CCL4 plasma concentrations in patients with chronic lymphocytic leukaemia managed with observation
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Sivina, Mariela, Werner, Lillian, Rassenti, Laura, Ferrajoli, Alessandra, Wierda, William G, Keating, Michael J, O'Brien, Susan, Neuberg, Donna, Kipps, Thomas, and Burger, Jan A
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Biomedical and Clinical Sciences ,Cardiovascular Medicine and Haematology ,Biomarkers ,Chemokine CCL3 ,Chemokine CCL4 ,Clinical Decision-Making ,Disease Management ,Humans ,Leukemia ,Lymphocytic ,Chronic ,B-Cell ,Watchful Waiting ,chronic lymphocytic leukaemia ,C-C motif chemokine ligands3 ,C-C motif chemokine ligands4 ,chemokines ,Cardiorespiratory Medicine and Haematology ,Immunology ,Cardiovascular medicine and haematology - Published
- 2018
10. The absolute percent deviation of IGHV mutation rather than a 98% cut‐off predicts survival of chronic lymphocytic leukaemia patients treated with fludarabine, cyclophosphamide and rituximab
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Jain, Preetesh, González, Graciela M Nogueras, Kanagal‐Shamanna, Rashmi, Rozovski, Uri, Sarwari, Nawid, Tam, Constantine, Wierda, William G, Thompson, Philip A, Jain, Nitin, Luthra, Rajyalakshmi, Quesada, Andres, Sanchez‐Petitto, Gabriela, Ferrajoli, Alessandra, Burger, Jan, Kantarjian, Hagop, Cortes, Jorge, O'Brien, Susan, Keating, Michael J, and Estrov, Zeev
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Biomedical and Clinical Sciences ,Cardiovascular Medicine and Haematology ,Oncology and Carcinogenesis ,Cancer ,Rare Diseases ,Hematology ,Clinical Research ,Lymphoma ,Adolescent ,Adult ,Aged ,Aged ,80 and over ,Antineoplastic Combined Chemotherapy Protocols ,Biomarkers ,Cyclophosphamide ,Female ,Humans ,Immunoglobulin Heavy Chains ,Immunoglobulin Variable Region ,Leukemia ,Myelogenous ,Chronic ,BCR-ABL Positive ,Male ,Middle Aged ,Mutation ,Neoplasm Staging ,Prognosis ,Proportional Hazards Models ,Rituximab ,Treatment Outcome ,Vidarabine ,Young Adult ,CLL ,FCR ,IGHV gene ,immunoglobulin heavy chain gene ,Cardiorespiratory Medicine and Haematology ,Immunology ,Cardiovascular medicine and haematology - Abstract
The degree of somatic hypermutation, determined as percent deviation of immunoglobulin heavy chain gene variable region sequence from the germline (IGHV%), is an important prognostic factor in chronic lymphocytic leukaemia (CLL). Currently, a cut-off of 2% deviation or 98% sequence identity to germline in IGHV sequence is routinely used to dichotomize CLL patients into mutated and unmutated groups. Because dissimilar IGHV% cut-offs of 1-5% were identified in different studies, we wondered whether no cut-off should be applied and IGHV% treated as a continuous variable. We analysed the significance of IGHV% in 203 CLL patients enrolled on the original frontline fludarabine, cyclophosphamide and rituximab (FCR) trial with a median of 10 years follow-up. Using the Cox Proportional Hazard model, IGHV% was identified as a continuous variable that is significantly associated with progression-free (PFS) and overall survival (OS) (P
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- 2018
11. Consolidation treatment with lenalidomide following front-line or salvage chemoimmunotherapy in chronic lymphocytic leukemia
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Strati, Paolo, Keating, Michael J, Burger, Jan A, O'Brien, Susan M, Wierda, William G, Estrov, Zeev, Zacharian, Gracy, and Ferrajoli, Alessandra
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Biomedical and Clinical Sciences ,Oncology and Carcinogenesis ,Adult ,Aged ,Consolidation Chemotherapy ,Female ,Humans ,Immunotherapy ,Lenalidomide ,Leukemia ,Lymphocytic ,Chronic ,B-Cell ,Male ,Middle Aged ,Cardiorespiratory Medicine and Haematology ,Immunology ,Cardiovascular medicine and haematology - Published
- 2017
12. Long-term Follow-up of Treatment with Ibrutinib and Rituximab in Patients with High-Risk Chronic Lymphocytic Leukemia
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Jain, Preetesh, Keating, Michael J, Wierda, William G, Sivina, Mariela, Thompson, Philip A, Ferrajoli, Alessandra, Estrov, Zeev, Kantarjian, Hagop, O'Brien, Susan, and Burger, Jan A
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Biomedical and Clinical Sciences ,Cardiovascular Medicine and Haematology ,Clinical Sciences ,Oncology and Carcinogenesis ,Rare Diseases ,Hematology ,Lymphoma ,Clinical Research ,Orphan Drug ,Clinical Trials and Supportive Activities ,Cancer ,Evaluation of treatments and therapeutic interventions ,6.2 Cellular and gene therapies ,6.1 Pharmaceuticals ,Adenine ,Adult ,Aged ,Antineoplastic Combined Chemotherapy Protocols ,Disease-Free Survival ,Female ,Follow-Up Studies ,Humans ,Leukemia ,Lymphocytic ,Chronic ,B-Cell ,Male ,Middle Aged ,Piperidines ,Pyrazoles ,Pyrimidines ,Remission Induction ,Rituximab ,Oncology & Carcinogenesis ,Clinical sciences ,Oncology and carcinogenesis - Abstract
Background: Ibrutinib is an active therapy with an acceptable safety profile for patients with chronic lymphocytic leukemia (CLL), including high-risk patients with del17p or with TP53 mutations. Ibrutinib is broadly indicated for the treatment of patients with CLL and specifically including those with 17p deletion. The optimal use of ibrutinib in combination with other agents remains controversial.Experimental Design: We report the long-term outcome [median follow-up of 47 months (range, 36-51 months)] of 40 patients with high-risk CLL, treated on the first ibrutinib combination trial with rituximab (IR). The majority of patients (36/40) were previously treated.Results: Median age was 65 years, and 21 patients (52%) had 17p deletion. Median duration on treatment was 41 months (range, 2-51 months), and median number of treatment cycles was 42 (range, 2-49). Overall response rate was 95%, and 9 patients (23%) attained a complete remission. Twenty-one patients discontinued treatment, 10 due to disease progression, 9 for other causes, and 2 due to stem cell transplantation; the remaining 19 patients continue on ibrutinib. Median progression-free survival for all patients was 45 months, which was significantly shorter in the subgroup of patients with del17p (n = 21, 32.3 months, P = 0.02). Fourteen patients (35%) died, five from progressive disease, five from infections, and four from other causes. Median overall survival has not been reached.Conclusions: IR combination therapy leads to durable remissions in high-risk CLL; the possible benefit from the addition of rituximab is currently explored in a randomized trial. Clin Cancer Res; 23(9); 2154-8. ©2016 AACR.
- Published
- 2017
13. Long-term follow-up of patients receiving allogeneic stem cell transplant for chronic lymphocytic leukaemia: mixed T-cell chimerism is associated with high relapse risk and inferior survival.
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Thompson, Philip A, Stingo, Francesco, Keating, Michael J, Wierda, William G, O'Brien, Susan M, Estrov, Zeev, Ledesma, Celina, Rezvani, Katayoun, Qazilbash, Muzaffar, Shah, Nina, Parmar, Simrit, Popat, Uday, Anderlini, Paolo, Yago, Nieto, Ciurea, Stefan O, Kebriaei, Partow, Champlin, Richard, Shpall, Elizabeth J, and Hosing, Chitra M
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T-Lymphocytes ,Humans ,Graft vs Host Disease ,Recurrence ,Immunosuppressive Agents ,Treatment Outcome ,Lymphocyte Transfusion ,Aftercare ,Stem Cell Transplantation ,Transplantation ,Homologous ,Epidemiologic Methods ,Graft Survival ,Chimerism ,Adult ,Aged ,Middle Aged ,Female ,Male ,Leukemia ,Lymphocytic ,Chronic ,B-Cell ,chronic lymphocytic leukaemia ,mixed chimerism ,relapse ,survival ,transplant ,Cancer ,Regenerative Medicine ,Hematology ,Transplantation ,Rare Diseases ,Clinical Research ,Cardiorespiratory Medicine and Haematology ,Immunology - Abstract
There is limited information regarding the immunological predictors of post-allogeneic stem cell transplant (alloSCT) outcome in chronic lymphocytic leukaemia (CLL), such as mixed T-cell chimerism. We analysed 143 consecutive patients with relapsed/refractory CLL, transplanted between 2000 and 2012, to determine the prognostic relevance of mixed chimerism post-alloSCT and the ability of post-transplant immunomodulation to treat relapse. Mixed T-cell chimerism occurred in 50% of patients at 3 months and 43% at 6 months post-alloSCT; upon 3- and 6-month landmark analysis, this was associated with inferior progression-free survival (PFS) [Hazard ratio (HR) 1·93, P = 0·003 and HR 2·58, P
- Published
- 2017
14. Constitutive Phosphorylation of STAT3 by the CK2–BLNK–CD5 Complex
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Rozovski, Uri, Harris, David M, Li, Ping, Liu, Zhiming, Jain, Preetesh, Veletic, Ivo, Ferrajoli, Alessandra, Burger, Jan, O'Brien, Susan, Bose, Prithviraj, Thompson, Philip, Jain, Nitin, Wierda, William, Keating, Michael J, and Estrov, Zeev
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Biochemistry and Cell Biology ,Biological Sciences ,Rare Diseases ,Lymphoma ,Hematology ,Biotechnology ,Cancer ,Adaptor Proteins ,Signal Transducing ,CD5 Antigens ,Casein Kinase II ,Cell Line ,Tumor ,Cell Membrane ,Cell Nucleus ,HeLa Cells ,Humans ,Jurkat Cells ,K562 Cells ,Leukemia ,Lymphocytic ,Chronic ,B-Cell ,Mass Spectrometry ,Phosphorylation ,STAT3 Transcription Factor ,Serine ,Hela Cells ,Oncology and Carcinogenesis ,Developmental Biology ,Oncology & Carcinogenesis ,Biochemistry and cell biology ,Oncology and carcinogenesis - Abstract
In chronic lymphocytic leukemia (CLL), STAT3 is constitutively phosphorylated on serine 727 and plays a role in the pathobiology of CLL. However, what induces constitutive phosphorylation of STAT3 is currently unknown. Mass spectrometry was used to identify casein kinase 2 (CK2), a serine/threonine kinase that coimmunoprecipitated with serine phosphorylated STAT3 (pSTAT3). Furthermore, activated CK2 incubated with recombinant STAT3 induced phosphorylation of STAT3 on serine 727. Although STAT3 and CK2 are present in normal B- and T cells, STAT3 is not constitutively phosphorylated in these cells. Further study found that CD5 and BLNK coexpressed in CLL, but not in normal B- or T cells, are required for STAT3 phosphorylation. To elucidate the relationship of CD5 and BLNK to CK2 and STAT3, STAT3 was immunoprecipitated from CLL cells, and CK2, CD5, and BLNK were detected in the immunoprecipitate. Conversely, STAT3, CD5, and BLNK were in the immunoprecipitate of CLL cells immunoprecipitated with CK2 antibodies. Furthermore, siRNA knockdown of CD5 or BLNK, or treatment with CD5-neutralizing antibodies significantly reduced the levels of serine pSTAT3 in CLL cells. Finally, confocal microscopy determined that CD5 is cell membrane bound, and fractionation studies revealed that the CK2/CD5/BLNK/STAT3 complex remains in the cytoplasm, whereas serine pSTAT3 is shuttled to the nucleus.Implications: These data show that the cellular proteins CK2, CD5, and BLNK are required for constitutive phosphorylation of STAT3 in CLL. Whether this protein complex phosphorylates other proteins or inhibiting its activity would have clinical benefit in patients has yet to be determined. Mol Cancer Res; 15(5); 610-8. ©2017 AACR.
- Published
- 2017
15. A phase I-II trial of fludarabine, bendamustine and rituximab (FBR) in previously treated patients with CLL
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Jain, Nitin, Balakrishnan, Kumudha, Ferrajoli, Alessandra, O’Brien, Susan M, Burger, Jan A, Kadia, Tapan M, Cortes, Jorge E, Ayres, Mary L, Tambaro, Francesco Paolo, Keating, Michael J, Gandhi, Varsha, and Wierda, William G
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Biomedical and Clinical Sciences ,Cardiovascular Medicine and Haematology ,Clinical Sciences ,Oncology and Carcinogenesis ,Clinical Research ,Clinical Trials and Supportive Activities ,Rare Diseases ,Cancer ,Hematology ,Lymphoma ,6.1 Pharmaceuticals ,Evaluation of treatments and therapeutic interventions ,6.2 Cellular and gene therapies ,Aged ,Aged ,80 and over ,Antineoplastic Combined Chemotherapy Protocols ,Bendamustine Hydrochloride ,Female ,Follow-Up Studies ,Humans ,Leukemia ,Lymphocytic ,Chronic ,B-Cell ,Male ,Middle Aged ,Neoplasm Staging ,Prognosis ,Rituximab ,Survival Rate ,Vidarabine ,CLL ,bendamustine ,chemoimmunotherapy ,fludarabine ,rituximab ,Oncology and carcinogenesis - Abstract
Chemoimmunotherapy regimens have been the standard first-line therapy for patients with chronic lymphocytic leukemia (CLL). For young, fit patients the standard of care is combination of fludarabine, cyclophosphamide, and rituximab (FCR). Based on the preclinical work demonstrating that bendamustine combined with fludarabine resulted in increased DNA damage, we designed a phase I-II clinical trial with fludarabine, bendamustine, and rituximab (FBR) for patients with relapsed/refractory CLL. Treatment consisted of fludarabine 20 mg/m2 daily x 3 days and rituximab 375-500 mg/m2 x 1 day. Phase I included bendamustine at increasing doses of 20, 30, 40, or 50 mg/m2 daily x 3 days; phase II was with FR, and B at the selected dose. DNA damage response (H2AX phosphorylation) was evaluated in a subset of patients. Fifty-one patients were enrolled. The median age was 62 years; median number of prior therapies was 2; 40% had del(11q); and 41 patients had received prior FCR-based therapies. Hematologic toxicity was more common in ≥40 mg/m2 dose cohorts. Maximum tolerated dose (MTD) was not identified. Bendamustine-elicited H2AX phosphorylation was not dose-dependent, but markedly increased after fludarabine. We identified bendamustine 30 mg/m2 as the safe dose for phase II. The overall response rate (ORR) was 67% with 36% complete response (CR) / CR with incomplete count recovery (CRi). Younger patients (
- Published
- 2017
16. Ibrutinib Therapy Increases T Cell Repertoire Diversity in Patients with Chronic Lymphocytic Leukemia
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Yin, Qingsong, Sivina, Mariela, Robins, Harlan, Yusko, Erik, Vignali, Marissa, O'Brien, Susan, Keating, Michael J, Ferrajoli, Alessandra, Estrov, Zeev, Jain, Nitin, Wierda, William G, and Burger, Jan A
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Biomedical and Clinical Sciences ,Oncology and Carcinogenesis ,Immunology ,Rare Diseases ,Orphan Drug ,Clinical Trials and Supportive Activities ,Hematology ,Clinical Research ,Cancer ,Lymphoma ,5.1 Pharmaceuticals ,Development of treatments and therapeutic interventions ,Adenine ,Aged ,B-Lymphocytes ,CD4-Positive T-Lymphocytes ,CD8-Positive T-Lymphocytes ,Cytokines ,High-Throughput Nucleotide Sequencing ,Humans ,Leukemia ,Lymphocytic ,Chronic ,B-Cell ,Piperidines ,Protein-Tyrosine Kinases ,Pyrazoles ,Pyrimidines ,Biochemistry and cell biology - Abstract
The Bruton's tyrosine kinase inhibitor ibrutinib is a highly effective, new targeted therapy for chronic lymphocytic leukemia (CLL) that thwarts leukemia cell survival, growth, and tissue homing. The effects of ibrutinib treatment on the T cell compartment, which is clonally expanded and thought to support the growth of malignant B cells in CLL, are not fully characterized. Using next-generation sequencing technology, we characterized the diversity of TCRβ-chains in peripheral blood T cells from 15 CLL patients before and after 1 y of ibrutinib therapy. We noted elevated CD4+ and CD8+ T cell numbers and a restricted TCRβ repertoire in all pretreatment samples. After 1 y of ibrutinib therapy, elevated peripheral blood T cell numbers and T cell-related cytokine levels had normalized, and T cell repertoire diversity increased significantly. Dominant TCRβ clones in pretreatment samples declined or became undetectable, and the number of productive unique clones increased significantly during ibrutinib therapy, with the emergence of large numbers of low-frequency TCRβ clones. Importantly, broader TCR repertoire diversity was associated with clinical efficacy and lower rates of infections during ibrutinib therapy. These data demonstrate that ibrutinib therapy increases diversification of the T cell compartment in CLL patients, which contributes to cellular immune reconstitution.
- Published
- 2017
17. Leukemia cell proliferation and death in chronic lymphocytic leukemia patients on therapy with the BTK inhibitor ibrutinib
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Burger, Jan A, Li, Kelvin W, Keating, Michael J, Sivina, Mariela, Amer, Ahmed M, Garg, Naveen, Ferrajoli, Alessandra, Huang, Xuelin, Kantarjian, Hagop, Wierda, William G, O’Brien, Susan, Hellerstein, Marc K, Turner, Scott M, Emson, Claire L, Chen, Shih-Shih, Yan, Xiao-Jie, Wodarz, Dominik, and Chiorazzi, Nicholas
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Rare Diseases ,Cancer ,Clinical Research ,Hematology ,Orphan Drug ,Clinical Trials and Supportive Activities ,Lymphoma ,Adenine ,Agammaglobulinaemia Tyrosine Kinase ,Aged ,Cell Death ,Cell Proliferation ,Deuterium Oxide ,Female ,Humans ,Leukemia ,Lymphocytic ,Chronic ,B-Cell ,Male ,Middle Aged ,Pilot Projects ,Piperidines ,Protein Kinase Inhibitors ,Pyrazoles ,Pyrimidines - Abstract
BACKGROUND. Ibrutinib is an effective targeted therapy for patients with chronic lymphocytic leukemia (CLL) that inhibits Bruton's tyrosine kinase (BTK), a kinase involved in B cell receptor signaling. METHODS. We used stable isotopic labeling with deuterated water (2H2O) to measure directly the effects of ibrutinib on leukemia cell proliferation and death in 30 patients with CLL. RESULTS. The measured average CLL cell proliferation ("birth") rate before ibrutinib therapy was 0.39% of the clone per day (range 0.17%-1.04%); this decreased to 0.05% per day (range 0%-0.36%) with treatment. Death rates of blood CLL cells increased from 0.18% per day (average, range 0%-0.7%) prior to treatment to 1.5% per day (range 0%-3.0%) during ibrutinib therapy, and they were even higher in tissue compartments. CONCLUSIONS. This study provides the first direct in vivo measurements to our knowledge of ibrutinib's antileukemia actions, demonstrating profound and immediate inhibition of CLL cell proliferation and promotion of high rates of CLL cell death. TRIAL REGISTRATION. This trial was registered at clinicaltrials.gov (NCT01752426). FUNDING. This study was supported by a Cancer Center Support Grant (National Cancer Institute grant P30 CA016672), an NIH grant (CA081554) from the National Cancer Institute, MD Anderson's Moon Shots Program in CLL, and Pharmacyclics, an AbbVie company.
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- 2017
18. Economic Burden of Chronic Lymphocytic Leukemia in the Era of Oral Targeted Therapies in the United States
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Chen, Qiushi, Jain, Nitin, Ayer, Turgay, Wierda, William G, Flowers, Christopher R, O'Brien, Susan M, Keating, Michael J, Kantarjian, Hagop M, and Chhatwal, Jagpreet
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Biomedical and Clinical Sciences ,Oncology and Carcinogenesis ,Rare Diseases ,Clinical Trials and Supportive Activities ,Dental/Oral and Craniofacial Disease ,Cost Effectiveness Research ,Hematology ,Comparative Effectiveness Research ,Clinical Research ,Cancer ,Lymphoma ,Good Health and Well Being ,Cost of Illness ,Cost-Benefit Analysis ,Costs and Cost Analysis ,Humans ,Leukemia ,Lymphocytic ,Chronic ,B-Cell ,Models ,Theoretical ,Quality of Life ,United States ,Clinical Sciences ,Oncology & Carcinogenesis ,Oncology and carcinogenesis - Abstract
Purpose Oral targeted therapies represent a significant advance for the treatment of patients with chronic lymphocytic leukemia (CLL); however, their high cost has raised concerns about affordability and the economic impact on society. Our objective was to project the future prevalence and cost burden of CLL in the era of oral targeted therapies in the United States. Methods We developed a simulation model that evaluated the evolving management of CLL from 2011 to 2025: chemoimmunotherapy (CIT) as the standard of care before 2014, oral targeted therapies for patients with del(17p) and relapsed CLL from 2014, and for first-line treatment from 2016 onward. A comparator scenario also was simulated where CIT remained the standard of care throughout. Disease progression and survival parameters for each therapy were based on published clinical trials. Results The number of people living with CLL in the United States is projected to increase from 128,000 in 2011 to 199,000 by 2025 (55% increase) due to improved survival; meanwhile, the annual cost of CLL management will increase from $0.74 billion to $5.13 billion (590% increase). The per-patient lifetime cost of CLL treatment will increase from $147,000 to $604,000 (310% increase) as oral targeted therapies become the first-line treatment. For patients enrolled in Medicare, the corresponding total out-of-pocket cost will increase from $9,200 to $57,000 (520% increase). Compared with the CIT scenario, oral targeted therapies resulted in an incremental cost-effectiveness ratio of $189,000 per quality-adjusted life-year. Conclusion The increased benefit and cost of oral targeted therapies is projected to enhance CLL survivorship but can impose a substantial financial burden on both patients and payers. More sustainable pricing strategies for targeted therapies are needed to avoid financial toxicity to patients.
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- 2017
19. Functional Differences between IgM and IgD Signaling in Chronic Lymphocytic Leukemia
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Ten Hacken, Elisa, Sivina, Mariela, Kim, Ekaterina, O'Brien, Susan, Wierda, William G, Ferrajoli, Alessandra, Estrov, Zeev, Keating, Michael J, Oellerich, Thomas, Scielzo, Cristina, Ghia, Paolo, Caligaris-Cappio, Federico, and Burger, Jan A
- Subjects
Biochemistry and Cell Biology ,Medical Physiology ,Biomedical and Clinical Sciences ,Biological Sciences ,Lymphoma ,Clinical Research ,Cancer ,Rare Diseases ,Hematology ,Adaptor Proteins ,Signal Transducing ,B-Lymphocytes ,Blood Proteins ,Cell Survival ,Cells ,Cultured ,Cellular Microenvironment ,Chemokine CCL3 ,Chemokine CCL4 ,Gene Expression Regulation ,Humans ,Immunoglobulin D ,Immunoglobulin M ,Intracellular Signaling Peptides and Proteins ,Leukemia ,Lymphocytic ,Chronic ,B-Cell ,Lymph Nodes ,Protein-Tyrosine Kinases ,Proto-Oncogene Proteins c-bcl-6 ,Receptors ,Antigen ,B-Cell ,Signal Transduction ,Immunology ,Biochemistry and cell biology - Abstract
BCR signaling is a central pathogenetic pathway in chronic lymphocytic leukemia (CLL). Most CLL cells express BCRs of IgM and IgD isotypes, but the contribution of these isotypes to functional responses remains incompletely defined. We therefore investigated differences between IgM and IgD signaling in freshly isolated peripheral blood CLL cells and in CLL cells cultured with nurselike cells, a model that mimics the lymph node microenvironment. IgM signaling induced prolonged activation of ERK kinases and promoted CLL cell survival, CCL3 and CCL4 chemokine secretion, and downregulation of BCL6, the transcriptional repressor of CCL3 In contrast, IgD signaling induced activation of the cytoskeletal protein HS1, along with F-actin polymerization, which resulted in rapid receptor internalization and failure to support downstream responses, including CLL cell survival and chemokine secretion. IgM and IgD receptor downmodulation, HS1 and ERK activation, chemokine secretion, and BCL6 downregulation were also observed when CLL cells were cocultured with nurselike cells. The Bruton's tyrosine kinase inhibitor ibrutinib effectively inhibited both IgM and IgD isotype signaling. In conclusion, through a variety of functional readouts, we demonstrate very distinct outcomes of IgM and IgD isotype activation in CLL cells, providing novel insight into the regulation of BCR signaling in CLL.
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- 2016
20. Outcomes of patients with chronic lymphocytic leukemia treated with first‐line idelalisib plus rituximab after cessation of treatment for toxicity
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Thompson, Philip A, Stingo, Francesco, Keating, Michael J, Ferrajoli, Alessandra, Burger, Jan A, Wierda, William G, Kadia, Tapan M, and O'Brien, Susan M
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Biomedical and Clinical Sciences ,Clinical Sciences ,Oncology and Carcinogenesis ,Patient Safety ,Clinical Research ,Lymphoma ,Rare Diseases ,Cancer ,Hematology ,6.1 Pharmaceuticals ,Evaluation of treatments and therapeutic interventions ,Aged ,Aged ,80 and over ,Antineoplastic Combined Chemotherapy Protocols ,Female ,Humans ,Leukemia ,Lymphocytic ,Chronic ,B-Cell ,Male ,Neoplasm Staging ,Purines ,Quinazolinones ,Rituximab ,Survival Analysis ,Treatment Outcome ,Withholding Treatment ,chronic lymphocytic leukemia ,disease-free survival ,idelalisib ,remission ,rituximab ,toxicity ,Public Health and Health Services ,Oncology & Carcinogenesis ,Oncology and carcinogenesis ,Public health - Abstract
BackgroundMore active therapies are needed for older and unfit patients with chronic lymphocytic leukemia (CLL) who are not eligible for chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab. The phosphyotidylinositol-3-kinase δ inhibitor idelalisib is effective in patients with treatment-naive and relapsed/refractory CLL as monotherapy and in combination with rituximab, but it can be associated with treatment-limiting adverse events, particularly diarrhea/colitis. The outcomes for patients who cease treatment for adverse events have not been previously described.MethodsThe authors analyzed long-term follow-up data from 40 treatment-naïve patients aged ≥65 years who received treatment at The University of Texas MD Anderson Cancer Center on a phase 2 study of idelalisib plus rituximab for CLL.ResultsIn patients who permanently ceased treatment because of toxicity, the time to subsequent disease progression was analyzed according to baseline characteristics. Fifteen patients permanently ceased therapy (PCT) because of toxicity (PCTTOX ), most commonly diarrhea/colitis (n = 7), at a median of 11 months after commencing treatment. PCTTOX was associated with a higher risk of subsequent disease progression (hazard ratio, 6.61; 95% confidence interval, 1.77-16.15) relative to that observed in patients who remained on therapy. Ten patients subsequently progressed, and 7 required salvage therapy; 5 patients remained progression-free at a median of 23.3 months (range, 8.5-28.6 months). Patients who were positive for ζ-associated protein-70 had more rapid disease progression after treatment cessation (P = .048). There were no CLL-related deaths.ConclusionsPCTTOX is the major determinant of PFS in patients who receive first-line idelalisib-based treatment. However, a subgroup of patients with favorable biologic characteristics has prolonged PFS, even after PCTTOX . The absence of CLL-related deaths indicates that salvage treatment is generally successful after PCTTOX . Cancer 2016;122:2505-11. © 2016 American Cancer Society.
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- 2016
21. Autoimmune cytopenias in patients with chronic lymphocytic leukemia treated with ibrutinib
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Vitale, Candida, Ahn, Inhye E, Sivina, Mariela, Ferrajoli, Alessandra, Wierda, William G, Estrov, Zeev, Konoplev, Sergej N, Jain, Nitin, O'Brien, Susan, Farooqui, Mohammed, Keating, Michael J, Wiestner, Adrian, and Burger, Jan A
- Subjects
Adenine ,Aged ,Anemia ,Autoimmune Diseases ,Humans ,Leukemia ,Lymphocytic ,Chronic ,B-Cell ,Male ,Middle Aged ,Piperidines ,Pyrazoles ,Pyrimidines ,autoimmune cytopenia ,chronic lymphochytic leukemia ,ibrutinib ,Immunology - Published
- 2016
22. Clonal evolution in patients with chronic lymphocytic leukaemia developing resistance to BTK inhibition.
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Burger, Jan A, Landau, Dan A, Taylor-Weiner, Amaro, Bozic, Ivana, Zhang, Huidan, Sarosiek, Kristopher, Wang, Lili, Stewart, Chip, Fan, Jean, Hoellenriegel, Julia, Sivina, Mariela, Dubuc, Adrian M, Fraser, Cameron, Han, Yulong, Li, Shuqiang, Livak, Kenneth J, Zou, Lihua, Wan, Youzhong, Konoplev, Sergej, Sougnez, Carrie, Brown, Jennifer R, Abruzzo, Lynne V, Carter, Scott L, Keating, Michael J, Davids, Matthew S, Wierda, William G, Cibulskis, Kristian, Zenz, Thorsten, Werner, Lillian, Dal Cin, Paola, Kharchencko, Peter, Neuberg, Donna, Kantarjian, Hagop, Lander, Eric, Gabriel, Stacey, O'Brien, Susan, Letai, Anthony, Weitz, David A, Nowak, Martin A, Getz, Gad, and Wu, Catherine J
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Humans ,Neoplasm Recurrence ,Local ,Pyrazoles ,Pyrimidines ,Apoptosis ,Drug Resistance ,Neoplasm ,Mutation ,Adult ,Aged ,80 and over ,Middle Aged ,Female ,Male ,Protein-Tyrosine Kinases ,Leukemia ,Lymphocytic ,Chronic ,B-Cell ,Cell Transdifferentiation ,Histiocytic Sarcoma ,Selection ,Genetic ,Clonal Evolution ,Agammaglobulinaemia Tyrosine Kinase ,Aged ,and over ,Drug Resistance ,Neoplasm ,Leukemia ,Lymphocytic ,Chronic ,B-Cell ,Neoplasm Recurrence ,Local ,Selection ,Genetic - Abstract
Resistance to the Bruton's tyrosine kinase (BTK) inhibitor ibrutinib has been attributed solely to mutations in BTK and related pathway molecules. Using whole-exome and deep-targeted sequencing, we dissect evolution of ibrutinib resistance in serial samples from five chronic lymphocytic leukaemia patients. In two patients, we detect BTK-C481S mutation or multiple PLCG2 mutations. The other three patients exhibit an expansion of clones harbouring del(8p) with additional driver mutations (EP300, MLL2 and EIF2A), with one patient developing trans-differentiation into CD19-negative histiocytic sarcoma. Using droplet-microfluidic technology and growth kinetic analyses, we demonstrate the presence of ibrutinib-resistant subclones and estimate subclone size before treatment initiation. Haploinsufficiency of TRAIL-R, a consequence of del(8p), results in TRAIL insensitivity, which may contribute to ibrutinib resistance. These findings demonstrate that the ibrutinib therapy favours selection and expansion of rare subclones already present before ibrutinib treatment, and provide insight into the heterogeneity of genetic changes associated with ibrutinib resistance.
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- 2016
23. Ofatumumab and Lenalidomide for Patients with Relapsed or Refractory Chronic Lymphocytic Leukemia: Correlation between Responses and Immune Characteristics
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Vitale, Candida, Falchi, Lorenzo, Hacken, Elisa ten, Gao, Hui, Shaim, Hila, Van Roosbroeck, Katrien, Calin, George, O'Brien, Susan, Faderl, Stefan, Wang, Xuemei, Wierda, William G, Rezvani, Katayoun, Reuben, James M, Burger, Jan A, Keating, Michael J, and Ferrajoli, Alessandra
- Subjects
Biomedical and Clinical Sciences ,Cardiovascular Medicine and Haematology ,Oncology and Carcinogenesis ,Emerging Infectious Diseases ,Cancer ,Infectious Diseases ,Hematology ,Clinical Research ,Rare Diseases ,Clinical Trials and Supportive Activities ,Evaluation of treatments and therapeutic interventions ,6.1 Pharmaceuticals ,Good Health and Well Being ,Adult ,Aged ,Aged ,80 and over ,Antibodies ,Monoclonal ,Antibodies ,Monoclonal ,Humanized ,Antineoplastic Agents ,Disease-Free Survival ,Female ,Humans ,Lenalidomide ,Leukemia ,Lymphocytic ,Chronic ,B-Cell ,Male ,Middle Aged ,Neoplasm Recurrence ,Local ,Thalidomide ,Treatment Outcome ,Oncology & Carcinogenesis ,Clinical sciences ,Oncology and carcinogenesis - Abstract
PurposeWe evaluated efficacy and tolerability of the combination of ofatumumab and lenalidomide in patients with relapsed/refractory chronic lymphocytic leukemia (CLL), and explored whether immune system characteristics could influence the response to treatment.Experimental designThirty-four patients were enrolled in this phase II study. Ofatumumab was administered at a dose of 300 mg on day 1, 1,000 mg on days 8, 15, and 22 during course 1, 1,000 mg on day 1 during courses 3-6, and once every other course during courses 7-24 (28-day courses). Oral lenalidomide (10 mg daily) was started on day 9 and continued for as long as a clinical benefit was observed.ResultsThe overall response rate was 71%. Eight patients (24%) achieved a complete remission (CR) or CR with incomplete recovery of blood counts, including 9% with minimal residual disease-negative CR. The median progression-free survival was 16 months, and the estimated 5-year survival was 53%. The most common treatment-related toxicity was neutropenia (grade >2 in 18% of the 574 patient courses). The most frequent infectious complications were pneumonia and neutropenic fever (24% and 9% of patients, respectively). We observed that patients who achieved a CR had at baseline higher numbers and a better preserved function of T cells and natural killer cells compared with non-responders.ConclusionsThe combination of ofatumumab and lenalidomide is a well-tolerated regimen that induces durable responses in the majority of patients with relapsed/refractory CLL. Our correlative data suggest a role of competent immune system in supporting the efficacy of this treatment. Clin Cancer Res; 22(10); 2359-67. ©2016 AACR.
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- 2016
24. β2‐microglobulin normalization within 6 months of ibrutinib‐based treatment is associated with superior progression‐free survival in patients with chronic lymphocytic leukemia
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Thompson, Philip A, O'Brien, Susan M, Xiao, Lianchun, Wang, Xuemei, Burger, Jan A, Jain, Nitin, Ferrajoli, Alessandra, Estrov, Zeev, Keating, Michael J, and Wierda, William G
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Biomedical and Clinical Sciences ,Oncology and Carcinogenesis ,Cancer ,Hematology ,Clinical Research ,Rare Diseases ,Adenine ,Adult ,Aged ,Aged ,80 and over ,Antineoplastic Combined Chemotherapy Protocols ,Bendamustine Hydrochloride ,Bone Marrow ,Case-Control Studies ,Chromosomes ,Human ,Pair 11 ,Chromosomes ,Human ,Pair 17 ,Cohort Studies ,Cyclophosphamide ,Disease-Free Survival ,Female ,Humans ,Immunoglobulin Heavy Chains ,Leukemia ,Lymphocytic ,Chronic ,B-Cell ,Male ,Middle Aged ,Neoplasm ,Residual ,Piperidines ,Prognosis ,Proportional Hazards Models ,Pyrazoles ,Pyrimidines ,Retrospective Studies ,Rituximab ,Treatment Outcome ,Vidarabine ,ZAP-70 Protein-Tyrosine Kinase ,beta 2-Microglobulin ,beta(2)-microglobulin ,BTK inhibitor ,chemoimmunotherapy ,chronic lymphocytic leukemia ,ibrutinib ,β2-microglobulin ,Public Health and Health Services ,Oncology & Carcinogenesis ,Oncology and carcinogenesis ,Public health - Abstract
BackgroundA high pretreatment β2 -microglobulin (B2M) level is associated with inferior survival outcomes in patients with chronic lymphocytic leukemia. However, to the authors' knowledge, the prognostic and predictive significance of changes in B2M during treatment have not been reported to date.MethodsThe authors analyzed 83 patients treated with ibrutinib-based regimens (66 with recurrent/refractory disease) and 198 treatment-naive patients who were treated with combined fludarabine, cyclophosphamide, and rituximab (FCR) to characterize changes in B2M and their relationship with clinical outcomes.ResultsB2M rapidly decreased during treatment with ibrutinib; on multivariable analysis, patients who received FCR (odds ratio, 0.40; 95% confidence interval [95% CI], 0.18-0.90 [P = .027]) were less likely to have normalized B2M at 6 months than patients treated with ibrutinib. On univariable analysis, normalization of B2M was associated with superior progression-free survival (PFS) from the 6-month landmark in patients treated with ibrutinib-based regimens and FCR. On multivariable analysis, failure to achieve normalized B2M at 6 months of treatment was associated with inferior PFS (hazard ratio, 16.9; 95% CI, 1.3-220.0 [P = .031]) for patients treated with ibrutinib, after adjusting for the effects of baseline B2M, stage of disease, fludarabine-refractory disease, and del(17p). In contrast, in patients treated with FCR, negative minimal residual disease status in the bone marrow was the only variable found to be significantly associated with superior PFS (hazard ratio, 0.28; 95% CI, 0.12-0.67 [P = .004]).ConclusionsNormalization of B2M at 6 months in patients treated with ibrutinib was found to be a useful predictor of subsequent PFS and may assist in clinical decision-making.
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- 2016
25. Externally validated predictive clinical model for untreated del(17p13.1) chronic lymphocytic leukemia patients
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Stephens, Deborah M, Ruppert, Amy S, Weirda, William G, Jones, Jeffrey A, Woyach, Jennifer A, Maddocks, Kami, Jaglowski, Samantha M, Andritsos, Leslie A, Flynn, Joseph M, Grever, Michael R, Lozanski, Gerard, Tam, Constantine, O'Brien, Susan, Keating, Michael J, Muthusamy, Natarajan, Abruzzo, Lynne V, Heerema, Nyla A, and Byrd, John C
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Biomedical and Clinical Sciences ,Oncology and Carcinogenesis ,Prevention ,Clinical Research ,Cancer ,Hematology ,Lymphoma ,Rare Diseases ,Detection ,screening and diagnosis ,4.1 Discovery and preclinical testing of markers and technologies ,Adult ,Aged ,Aged ,80 and over ,Antineoplastic Agents ,Base Sequence ,Chromosomes ,Human ,Pair 17 ,Female ,Humans ,Karyotype ,Leukemia ,Lymphocytic ,Chronic ,B-Cell ,Male ,Middle Aged ,Molecular Sequence Data ,Prognosis ,Proportional Hazards Models ,Retrospective Studies ,Risk ,Sequence Deletion ,Survival Analysis ,Cardiorespiratory Medicine and Haematology ,Immunology ,Cardiovascular medicine and haematology - Abstract
Little is known about outcomes of patients with chronic lymphocytic leukemia (CLL) with del(17p13.1) karyotype at diagnosis. We reviewed 114 de novo del(17p13.1) CLL patients seen at our institution. Using proportional hazards models to identify pretreatment clinical variables significantly associated with treatment-free survival (TFS) and overall survival (OS), we developed a simplified risk score for de novo del(17p13.1) CLL patients to predict TFS and OS based on these variables. These scores, particularly the very highest, can be utilized to identify high-risk patients for expedient enrollment on clinical trials. Our data support careful observation for low-risk patients, potentially preventing unnecessary use of aggressive therapies.
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- 2015
26. Fludarabine, cyclophosphamide, and multiple‐dose rituximab as frontline therapy for chronic lymphocytic leukemia
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Short, Nicholas J, Keating, Michael J, Wierda, William G, Faderl, Stefan, Ferrajoli, Alessandra, Estrov, Zeev, Smith, Susan C, and O'Brien, Susan M
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Rare Diseases ,Stem Cell Research - Nonembryonic - Human ,Hematology ,Cancer ,Stem Cell Research ,Clinical Trials and Supportive Activities ,Clinical Research ,Lymphoma ,Infectious Diseases ,6.1 Pharmaceuticals ,Evaluation of treatments and therapeutic interventions ,6.2 Cellular and gene therapies ,Adult ,Aged ,Aged ,80 and over ,Cyclophosphamide ,Disease Progression ,Dose-Response Relationship ,Drug ,Drug Therapy ,Combination ,Female ,Follow-Up Studies ,Humans ,Leukemia ,Lymphocytic ,Chronic ,B-Cell ,Male ,Middle Aged ,Rituximab ,Survival Rate ,Treatment Outcome ,Vidarabine ,chemoimmunotherapy ,chronic lymphocytic leukemia ,fludarabine ,cyclophosphamide ,and rituximab ,rituximab ,therapy-related acute myelogenous leukemia ,therapy-related myelodysplastic syndrome ,Oncology and Carcinogenesis ,Public Health and Health Services ,Oncology & Carcinogenesis - Abstract
BackgroundFludarabine, cyclophosphamide, and rituximab (FCR) result in durable responses in patients with previously untreated chronic lymphocytic leukemia (CLL). Previous reports have suggested that in patients with relapsed CLL, a dose-intensified rituximab regimen increases response rates in comparison with standard-dose rituximab. It is unknown whether rituximab intensification of the FCR regimen will result in improved response rates and patient outcomes in patients with previously untreated CLL.MethodsA single-arm study was conducted to evaluate the safety and efficacy of a modified FCR regimen with multiple-dose rituximab (FCR3) in 65 patients with previously untreated CLL. The results were compared with those for a historical cohort treated with FCR.ResultsThe overall response rate to FCR3 was 97%, with 75% of the patients achieving a complete remission. Minimal residual disease negativity was achieved for 62% of the patients according to flow cytometry. The median time to progression (TTP) was 81 months, and the median overall survival (OS) was not reached, with 58% of the patients still alive at a median survivor follow-up of 9.7 years. Grade 3 or 4 neutropenia, grade 3 or 4 thrombocytopenia, and major infections were observed with 45%, 5%, and 1.9% of the FCR3 courses, respectively. Therapy-related myelodysplastic syndrome (t-MDS) or therapy-related acute myelogenous leukemia (t-AML) developed in 7 patients (11%; P < .01 vs the historical FCR cohort).ConclusionsIn patients with previously untreated CLL, FCR3 resulted in response rates, TTP, and OS similar to those of a historical cohort of patients treated with FCR. FCR3 was associated with an increased incidence of t-MDS/t-AML.
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- 2015
27. Complex karyotype is a stronger predictor than del(17p) for an inferior outcome in relapsed or refractory chronic lymphocytic leukemia patients treated with ibrutinib‐based regimens
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Thompson, Philip A, O'Brien, Susan M, Wierda, William G, Ferrajoli, Alessandra, Stingo, Francesco, Smith, Susan C, Burger, Jan A, Estrov, Zeev, Jain, Nitin, Kantarjian, Hagop M, and Keating, Michael J
- Subjects
Rare Diseases ,Orphan Drug ,Hematology ,Cancer ,Clinical Research ,Lymphoma ,Abnormal Karyotype ,Adenine ,Adult ,Aged ,Aged ,80 and over ,Antineoplastic Agents ,Chromosome Deletion ,Chromosomes ,Human ,Pair 17 ,Cytogenetic Analysis ,Female ,Humans ,Leukemia ,Lymphocytic ,Chronic ,B-Cell ,Male ,Middle Aged ,Neoplasm Recurrence ,Local ,Piperidines ,Pyrazoles ,Pyrimidines ,Survival Analysis ,Treatment Outcome ,chronic lymphocytic leukemia ,complex karyotype ,del(17p) ,ibrutinib ,relapsed and refractory ,Oncology and Carcinogenesis ,Public Health and Health Services ,Oncology & Carcinogenesis - Abstract
BackgroundIbrutinib is active in patients with relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL). In patients treated with ibrutinib for R/R CLL, del(17p), identified by interphase fluorescence in situ hybridization (FISH), is associated with inferior progression-free survival despite equivalent initial response rates. Del(17p) is frequently associated with a complex metaphase karyotype (CKT); the prognostic significance of CKT in ibrutinib-treated patients has not been reported.MethodsThis study reviewed 88 patients treated for R/R CLL at The University of Texas MD Anderson Cancer Center with investigational ibrutinib-based regimens from 2010 to 2013. Pretreatment FISH and lipopolysaccharide-stimulated metaphase cytogenetic analysis were performed on bone marrow.ResultsAn adequate pretreatment metaphase karyotype was available for 56 of the 88 patients. The karyotype was complex in 21 of the 56 cases; 17 of the 21 had del(17p) according to FISH. The overall response rate, including partial remission with persistent lymphocytosis, was 94%; 18% had complete responses. In a multivariate analysis (MVA), only CKT was significantly associated with event-free survival (EFS; hazard ratio [HR], 6.6 [95% CI 1.7-25.6]; P = .006). Fludarabine-refractory CLL (HR, 6.9 [95% CI 1.8-27.1], P = .005) and CKT (HR 5.9 [95% CI 1.6-22.2], P = .008) were independently associated with inferior overall survival (OS) in MVA. Del(17p) by FISH was not significantly associated with EFS or OS in MVA.ConclusionsCKT is a powerful predictor of outcomes for ibrutinib-treated patients with R/R CLL and may be a stronger predictor of biological behavior than del(17p) by FISH. Because of their relatively poor outcomes, patients with CKT are ideal candidates for studies of consolidative treatment strategies or novel treatment combinations.
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- 2015
28. Second Cancers and Richter Transformation Are the Leading Causes of Death in Patients With Trisomy 12 Chronic Lymphocytic Leukemia
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Strati, Paolo, Abruzzo, Lynne V, Wierda, William G, O'Brien, Susan, Ferrajoli, Alessandra, and Keating, Michael J
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Biomedical and Clinical Sciences ,Cardiovascular Medicine and Haematology ,Oncology and Carcinogenesis ,Genetics ,Cancer ,Prevention ,Hematology ,Rare Diseases ,Clinical Research ,ADP-ribosyl Cyclase 1 ,Aged ,Aged ,80 and over ,Cause of Death ,Chromosomes ,Human ,Pair 12 ,Female ,Humans ,In Situ Hybridization ,Fluorescence ,Leukemia ,Lymphocytic ,Chronic ,B-Cell ,Lymphoma ,Large B-Cell ,Diffuse ,Male ,Membrane Glycoproteins ,Neoplasms ,Second Primary ,Retrospective Studies ,Thrombocytopenia ,Trisomy ,CLL ,Prognosis ,Richter transformation ,Second cancers ,Trisomy 12 ,Clinical Sciences ,Cardiovascular medicine and haematology ,Oncology and carcinogenesis - Abstract
BackgroundTrisomy 12 (+12) is detected by fluorescence in-situ hybridization (FISH) analysis in up to 20% of patients with chronic lymphocytic leukemia (CLL). Patients with +12 are known to have unique features and to carry an intermediate prognosis.Patients and methodsIn order to better define this large group, we reviewed the characteristics of 250 untreated patients with +12.ResultsWhen compared to 516 untreated patients negative for +12 by FISH, patients with +12 showed a higher incidence of thrombocytopenia, Richter transformation, and second malignant neoplasms (SMN), in addition to the expected increased rate of CD38 positivity and atypical immunophenotype. At a median follow-up of 51 months, 57% of patients needed first-line treatment; median time to first treatment was 38 months, and on multivariate analysis (MVA), it was found to be shorter in patients with advanced Rai stage, palpable splenomegaly, and deletion of 14q by conventional cytogenetic analysis. The overall response rate with first-line treatment was 94%. The median failure-free survival has not been reached, but on MVA, it was found to be shorter in patients whose disease responded in a manner other than complete remission or with FISH negativity for deletion 13q. The median overall survival for the entire group has not been reached, but MVA revealed it to be shorter in patients with an absolute lymphocyte count of > 30 × 10(9)/L or who developed SMN. Eighteen deaths have been observed so far, and Richter transformation and SMN were the leading causes of death (3 and 6, respectively).ConclusionPatients with +12 CLL show characteristic clinical and biologic features, and may benefit from increased surveillance for second cancers.
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- 2015
29. Three Newly Approved Drugs for Chronic Lymphocytic Leukemia: Incorporating Ibrutinib, Idelalisib, and Obinutuzumab into Clinical Practice
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Sanford, David S, Wierda, William G, Burger, Jan A, Keating, Michael J, and O'Brien, Susan M
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Biomedical and Clinical Sciences ,Oncology and Carcinogenesis ,Cancer ,Rare Diseases ,Clinical Research ,Hematology ,Orphan Drug ,Lymphoma ,Development of treatments and therapeutic interventions ,6.1 Pharmaceuticals ,Evaluation of treatments and therapeutic interventions ,5.1 Pharmaceuticals ,Adenine ,Antibodies ,Monoclonal ,Humanized ,Antineoplastic Agents ,Humans ,Leukemia ,Lymphocytic ,Chronic ,B-Cell ,Piperidines ,Purines ,Pyrazoles ,Pyrimidines ,Quinazolinones ,Anti-CD20 antibody ,BTK inhibitor ,Lymphoid malignancy ,Novel agents ,PI3K inhibitor ,Clinical Sciences ,Cardiovascular medicine and haematology ,Oncology and carcinogenesis - Abstract
Three agents have received Food and Drug Administration (FDA) approval for treatment of chronic lymphocytic leukemia (CLL) within the past year. Ibrutinib and idelalisib block B-cell receptor signaling through inhibition of Bruton tyrosine kinase and phosphatidylinositol 3-kinase δ molecules respectively, interfering with several pathways required for leukemia cell survival. Idelalisib has shown efficacy in the relapsed setting and is currently approved by the FDA for use in combination with rituximab. Ibrutinib has been studied in patients with relapsed CLL and as frontline therapy. In the relapsed setting, these agents produce durable remissions, and might be preferable to re-treatment with chemoimmunotherapy for many patients. Ibrutinib is also effective treatment for patients with deletion 17p and is approved by the FDA as frontline therapy in this patient group, although it does not appear to completely abrogate this adverse prognostic factor. These agents have a unique side effect profile and longer follow-up is required to further understand tolerability and rare adverse effects. Obinutuzumab is a type-2 monoclonal anti-CD20 antibody which results in direct and antibody-dependent cell-mediated cytotoxicity of leukemia cells. It is approved by the FDA for use in combination with chlorambucil, and has shown efficacy in the frontline setting in patients unfit for more intensive chemoimmunotherapy. It produces increased response rates and minimal residual disease negativity compared with chlorambucil/rituximab and is associated with an advantage in progression-free survival but not yet overall survival. These agents underscore our advancement in the understanding of the biology of CLL and will improve outcomes for many patients with CLL.
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- 2015
30. Outcomes of Patients With Chronic Lymphocytic Leukemia and Richter's Transformation After Transplantation Failure
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Rozovski, Uri, Benjamini, Ohad, Jain, Preetesh, Thompson, Philip A, Wierda, William G, O'Brien, Susan, Burger, Jan A, Ferrajoli, Alessandra, Faderl, Stefan, Shpall, Elizabeth, Hosing, Chitra, Khouri, Issa F, Champlin, Richard, Keating, Michael J, and Estrov, Zeev
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Biomedical and Clinical Sciences ,Cardiovascular Medicine and Haematology ,Oncology and Carcinogenesis ,Genetics ,Cancer ,Transplantation ,Hematology ,Rare Diseases ,Orphan Drug ,Clinical Research ,Lymphoma ,Adenine ,Adult ,Aged ,Antineoplastic Agents ,Chronic Disease ,Disease Progression ,Factor Analysis ,Statistical ,Female ,Graft vs Host Disease ,Humans ,Kaplan-Meier Estimate ,Leukemia ,Lymphocytic ,Chronic ,B-Cell ,Male ,Middle Aged ,Piperidines ,Pyrazoles ,Pyrimidines ,Recurrence ,Retrospective Studies ,Risk Factors ,Salvage Therapy ,Stem Cell Transplantation ,Transplantation Conditioning ,Transplantation ,Homologous ,Treatment Failure ,Treatment Outcome ,Clinical Sciences ,Oncology & Carcinogenesis ,Oncology and carcinogenesis - Abstract
PurposeAllogeneic stem-cell transplantation (SCT) induces long-term remission in a fraction of patients with high-risk chronic lymphocytic leukemia (CLL) or Richter's transformation (RT). Our purpose was to determine the outcomes of patients whose disease progressed after allogeneic SCT.Patients and methodsWe retrospectively analyzed the outcomes of 72 patients (52 with CLL and 20 with RT) who underwent allogeneic SCT between 1998 and 2011 and had documented progression after transplantation. Twenty-two (31%) never had a response, and 50 (69%) had a response but experienced relapse after a median of 7 months (range, 2 to 85 months). Forty-eight patients who were receiving or were candidates to receive post-SCT cell-based therapies were not included in this analysis.ResultsThe median age at time of transplantation was 58 years (range, 30 to 72 years). Sixty-two patients (86%) received more than two treatment regimens and 37 (51%) received more than three treatment regimens before SCT. Sixty-six patients (92%) had active disease at the time of transplantation. The 2- and 5-year survival rates were 67% and 38% (patients with CLL) and 36% and 0% (patients with RT). The patients who developed acute or chronic graft-versus-host disease had a longer overall survival (OS; P = .05). In a multivariable analysis, RT or low hemoglobin at the time of SCT predicted shorter OS. Chronic graft-versus-host disease and an initial response to SCT predicted longer OS.ConclusionPatients with CLL in whom allogeneic SCT fails may have a response to and benefit from salvage therapies, and their prognosis is relatively good.
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- 2015
31. Aberrant LPL Expression, Driven by STAT3, Mediates Free Fatty Acid Metabolism in CLL Cells
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Rozovski, Uri, Grgurevic, Srdana, Bueso-Ramos, Carlos, Harris, David M, Li, Ping, Liu, Zhiming, Wu, Ji Yuan, Jain, Preetesh, Wierda, William, Burger, Jan, O'Brien, Susan, Jain, Nitin, Ferrajoli, Alessandra, Keating, Michael J, and Estrov, Zeev
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Biochemistry and Cell Biology ,Biological Sciences ,Genetics ,Hematology ,Cancer ,Lymphoma ,Rare Diseases ,Underpinning research ,1.1 Normal biological development and functioning ,Fatty Acids ,Nonesterified ,Humans ,Leukemia ,Lymphocytic ,Chronic ,B-Cell ,Lipoprotein Lipase ,STAT3 Transcription Factor ,Transfection ,Oncology and Carcinogenesis ,Developmental Biology ,Oncology & Carcinogenesis ,Biochemistry and cell biology ,Oncology and carcinogenesis - Abstract
UnlabelledWhile reviewing chronic lymphocytic leukemia (CLL) bone marrow slides, we identified cytoplasmic lipid vacuoles in CLL cells but not in normal B cells. Because lipoprotein lipase (LPL), which catalyzes hydrolysis of triglycerides into free fatty acids (FFA), is aberrantly expressed in CLL, we investigated whether LPL regulates the oxidative metabolic capacity of CLL cells. We found that unlike normal B cells, CLL cells metabolize FFAs. Because STAT3 is constitutively activated in CLL cells and because we identified putative STAT3 binding sites in the LPL promoter, we sought to determine whether STAT3 drives the aberrant expression of LPL. Transfection of luciferase reporter gene constructs driven by LPL promoter fragments into MM1 cells revealed that STAT3 activates the LPL promoter. In addition, chromatin immunoprecipitation confirmed that STAT3 binds to the LPL promoter. Furthermore, transfection of CLL cells with STAT3-shRNA downregulated LPL transcripts and protein levels, confirming that STAT3 activates the LPL gene. Finally, transfection of CLL cells with LPL-siRNAs decreased the capacity of CLL cells to oxidize FFAs and reduced cell viability.ImplicationsOur study suggests that CLL cells adopt their metabolism to oxidize FFA. Activated STAT3 induces LPL, which catalyzes the hydrolysis of triglycerides into FFA. Therefore, inhibition of STAT3 is likely to prevent the capacity of CLL cells to utilize FFA.
- Published
- 2015
32. A Phase I Study of Fludarabine, Cytarabine, and Oxaliplatin Therapy in Patients With Relapsed or Refractory Acute Myeloid Leukemia
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Tsimberidou, Apostolia Maria, Keating, Michael J, Jabbour, Elias J, Ravandi-Kashani, Farhad, O'Brien, Susan, Estey, Elihu, Bekele, Neby, Plunkett, William K, Kantarjian, Hagop, and Borthakur, Gautam
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Biomedical and Clinical Sciences ,Clinical Sciences ,Oncology and Carcinogenesis ,Cancer ,Rare Diseases ,Clinical Research ,Patient Safety ,Pediatric Cancer ,Childhood Leukemia ,Clinical Trials and Supportive Activities ,Orphan Drug ,Pediatric ,Hematology ,6.1 Pharmaceuticals ,6.2 Cellular and gene therapies ,Evaluation of treatments and therapeutic interventions ,Adolescent ,Adult ,Aged ,Antineoplastic Combined Chemotherapy Protocols ,Child ,Cytarabine ,Dose-Response Relationship ,Drug ,Drug Administration Schedule ,Female ,Gastrointestinal Diseases ,Humans ,Hyperbilirubinemia ,Leukemia ,Myeloid ,Acute ,Male ,Middle Aged ,Organoplatinum Compounds ,Oxaliplatin ,Remission Induction ,Salvage Therapy ,Treatment Outcome ,Vidarabine ,Young Adult ,DLT ,High-risk MDS ,Poor-risk ,Response ,Toxicity ,Cardiovascular medicine and haematology ,Oncology and carcinogenesis - Abstract
PurposeThe combination of cytarabine and fludarabine was associated with superior clinical outcomes compared with those of high-dose cytarabine in relapse acute myeloid leukemia (AML). We conducted a phase I study combining oxaliplatin with cytarabine and fludarabine therapy for patients with relapsed or refractory AML.Patients and methodsBetween January 2008 and November 2009, 27 patients were registered in the study. Patients had histologically confirmed disease, performance status 0 to 2, and adequate organ function. The treatment regimen consisted of increasing doses of oxaliplatin (25, 30, or 35 mg/m(2)/d) on days 1 to 4 (escalation phase), and fludarabine (30 mg/m²) and cytarabine (500 mg/m²) on days 2 to 6, every 28 days for ≤ 6 cycles. The dose-limiting toxicity was defined as any symptomatic grade ≥ 3 nonhematologic toxicity lasting ≥ 3 days and involving a major organ system.ResultsOf 27 patients, 12 were treated in the dose-escalation phase and 15 at the maximum tolerated dose for oxaliplatin (30 mg/m²; expansion phase). All patients were evaluable for toxicity and response. Only 1 patient received the second cycle; the remaining patients received no further study treatment, owing to slow recovery from toxicities or physician decision. Grade 3-4 drug-related toxicities included diarrhea (grade 4) and elevated levels of bilirubin (grade 3) and aspartate transaminase (grade 3). In all, 3 patients had a complete remission and 2 patients complete response without platelet recovery.ConclusionOxaliplatin, cytarabine, and fludarabine therapy had antileukemic activity in patients with poor-risk AML, but it was associated with toxicity. Different schedules and doses may be better tolerated.
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- 2014
33. Safety and activity of ibrutinib plus rituximab for patients with high-risk chronic lymphocytic leukaemia: a single-arm, phase 2 study
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Burger, Jan A, Keating, Michael J, Wierda, William G, Hartmann, Elena, Hoellenriegel, Julia, Rosin, Nathalie Y, de Weerdt, Iris, Jeyakumar, Ghayathri, Ferrajoli, Alessandra, Cardenas-Turanzas, Marylou, Lerner, Susan, Jorgensen, Jeffrey L, Nogueras-González, Graciela M, Zacharian, Gracy, Huang, Xuelin, Kantarjian, Hagop, Garg, Naveen, Rosenwald, Andreas, and O'Brien, Susan
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Biomedical and Clinical Sciences ,Cardiovascular Medicine and Haematology ,Oncology and Carcinogenesis ,Rare Diseases ,Clinical Trials and Supportive Activities ,Hematology ,Clinical Research ,Patient Safety ,Cancer ,Lymphoma ,6.2 Cellular and gene therapies ,6.1 Pharmaceuticals ,Evaluation of treatments and therapeutic interventions ,Adenine ,Administration ,Oral ,Adult ,Aged ,Aged ,80 and over ,Antibodies ,Monoclonal ,Antibodies ,Monoclonal ,Murine-Derived ,Antineoplastic Combined Chemotherapy Protocols ,Disease-Free Survival ,Dose-Response Relationship ,Drug ,Drug Administration Schedule ,Female ,Humans ,Kaplan-Meier Estimate ,Leukemia ,Lymphocytic ,Chronic ,B-Cell ,Male ,Maximum Tolerated Dose ,Middle Aged ,Neoplasm Recurrence ,Local ,Patient Selection ,Piperidines ,Prognosis ,Pyrazoles ,Pyrimidines ,Rituximab ,Survival Rate ,Treatment Outcome ,Oncology & Carcinogenesis ,Oncology and carcinogenesis - Abstract
BackgroundIbrutinib, an orally administered covalent inhibitor of Bruton's tyrosine kinase (BTK), is an effective treatment for relapsed chronic lymphocytic leukaemia (CLL). We investigated the activity and safety of the combination of ibrutinib with the monoclonal antibody rituximab in patients with high-risk CLL.MethodsIn this single-arm phase 2 study, we enrolled adult patients with high-risk CLL at the MD Anderson Cancer Center (Houston, TX, USA). All enrolled participants had high-risk cytogenetic abnormalities (deletion 17p, TP53 mutation, or deletion 11q) or a short progression-free survival (PFS
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- 2014
34. Outcomes of first-line treatment for chronic lymphocytic leukemia with 17p deletion
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Strati, Paolo, Keating, Michael J, O'Brien, Susan M, Ferrajoli, Alessandra, Burger, Jan, Faderl, Stefan, Tambaro, Francesco Paolo, Jain, Nitin, and Wierda, William G
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Biomedical and Clinical Sciences ,Cardiovascular Medicine and Haematology ,Oncology and Carcinogenesis ,Rare Diseases ,Hematology ,Cancer ,Adult ,Aged ,Aged ,80 and over ,Antibodies ,Monoclonal ,Murine-Derived ,Antineoplastic Combined Chemotherapy Protocols ,Chromosome Deletion ,Chromosomes ,Human ,Pair 17 ,Disease-Free Survival ,Female ,Follow-Up Studies ,Humans ,Lenalidomide ,Leukemia ,Lymphocytic ,Chronic ,B-Cell ,Male ,Middle Aged ,Retrospective Studies ,Rituximab ,Smith-Magenis Syndrome ,Thalidomide ,Treatment Outcome ,Cardiorespiratory Medicine and Haematology ,Immunology ,Cardiovascular medicine and haematology - Abstract
Although uncommon in treatment-naive patients with chronic lymphocytic leukemia, deletion 17p is a high-risk disease characteristic. We analyzed and reported outcomes for 63 patients with deletion 17p chronic lymphocytic leukemia who received first-line therapy at our institution; at time of first treatment, 81% had unmutated immunoglobulin heavy chain variable gene and 58% had complex karyotype. Forty-nine patients (76%) received first-line fludarabine, cyclophosphamide, rituximab-based therapy, 6 (11%) received rituximab-based and 8 (13%) received lenalidomide-based treatment. Overall, the complete plus nodular partial remission rate was 33%; on multivariable model, higher complete plus nodular partial remission rate was observed in patients with less than 50% cells positive for deletion 17p, and a higher probability of achieving at least a partial remission was observed with fludarabine, cyclophosphamide, rituximab-based treatment. After a median follow up of 33 months (range 1-89 months), the estimated median progression-free survival was 14 months (95% confidence interval 10-18) and estimated median overall survival was 63 months (95% confidence interval 43-83). In multivariable analysis, factors independently associated with longer progression-free survival were response to treatment and absence of complex karyotype. Achievement of complete plus nodular partial remission rate and mutated immunoglobulin heavy chain variable gene were independently associated with longer overall survival in multivariable model. Complex karyotype was associated with increased risk for Richter's transformation. New first-line strategies and agents must aim at both improving response and maintaining remission in patients with deletion 17p, particularly in the presence of complex karyotype.
- Published
- 2014
35. Fludarabine, cyclophosphamide and rituximab plus granulocyte macrophage colony-stimulating factor as frontline treatment for patients with chronic lymphocytic leukemia
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Strati, Paolo, Ferrajoli, Alessandra, Lerner, Susan, O’Brien, Susan, Wierda, William, Keating, Michael J, and Faderl, Stefan
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Biomedical and Clinical Sciences ,Cardiovascular Medicine and Haematology ,Rare Diseases ,Infectious Diseases ,Clinical Trials and Supportive Activities ,Hematology ,Clinical Research ,Cancer ,Lymphoma ,6.1 Pharmaceuticals ,Evaluation of treatments and therapeutic interventions ,Good Health and Well Being ,Adolescent ,Adult ,Aged ,Aged ,80 and over ,Antibodies ,Monoclonal ,Murine-Derived ,Antineoplastic Combined Chemotherapy Protocols ,Cyclophosphamide ,Female ,Granulocyte-Macrophage Colony-Stimulating Factor ,Humans ,Leukemia ,Lymphocytic ,Chronic ,B-Cell ,Male ,Middle Aged ,Neoplasm Staging ,Rituximab ,Treatment Outcome ,Vidarabine ,Young Adult ,Clinical Sciences ,Immunology ,Cardiovascular medicine and haematology - Abstract
Fludarabine, cyclophosphamide and rituximab (FCR), the standard of care for the frontline treatment of patients with chronic lymphocytic leukemia (CLL), is associated with a high rate of neutropenia and infectious complications. Granulocyte macrophage colony-stimulating factor (GM-CSF) reduces myelosuppression and can potentiate rituximab activity. We conducted a clinical trial combining GM-CSF with FCR for frontline treatment of 60 patients with CLL. Eighty-six percent completed all six courses and 18% discontinued GM-CSF for toxicity: grade 3-4 neutropenia was observed in 30% of cycles, and severe infections in 16% of cases. The overall response rate was 100%. Both median event-free survival (EFS) and overall survival (OS) have not been reached. Longer EFS was associated with favorable cytogenetics. GM-CSF led to a lower frequency of infectious complications than in the historical FCR group, albeit similar EFS and OS.
- Published
- 2014
36. Myelosuppression after frontline fludarabine, cyclophosphamide, and rituximab in patients with chronic lymphocytic leukemia
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Strati, Paolo, Wierda, William, Burger, Jan, Ferrajoli, Alessandra, Tam, Constantine, Lerner, Susan, Keating, Michael J, and O'Brien, Susan
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Biomedical and Clinical Sciences ,Clinical Sciences ,Oncology and Carcinogenesis ,Hematology ,Clinical Research ,Rare Diseases ,Patient Safety ,Cancer ,Evaluation of treatments and therapeutic interventions ,6.1 Pharmaceuticals ,Adolescent ,Adult ,Aged ,Aged ,80 and over ,Antibodies ,Monoclonal ,Murine-Derived ,Antineoplastic Combined Chemotherapy Protocols ,Clinical Trials ,Phase II as Topic ,Cyclophosphamide ,Female ,Humans ,Immune Tolerance ,Immunotherapy ,Leukemia ,Lymphocytic ,Chronic ,B-Cell ,Male ,Middle Aged ,Myeloablative Agonists ,Neoadjuvant Therapy ,Pancytopenia ,Retrospective Studies ,Rituximab ,Treatment Outcome ,Vidarabine ,Young Adult ,chronic lymphocytic leukemia ,combination of fludarabine ,cyclophosphamide ,and rituximab ,cytopenia ,prognosis ,Public Health and Health Services ,Oncology & Carcinogenesis ,Oncology and carcinogenesis ,Public health - Abstract
BackgroundThe combination of fludarabine, cyclophosphamide, and rituximab (FCR) has produced improved response rates and a prolonged survival in patients with chronic lymphocytic leukemia (CLL). However, its therapeutic power is counterbalanced by significant hematologic toxicity. Persistent and new-onset cytopenia after the completion of FCR raise concern about disease recurrence, the development of therapy-related myeloid malignancies (TRMM), and infections.MethodsA total of 207 patients with CLL who achieved complete response, complete response with incomplete bone marrow recovery, or nodular partial remission were analyzed after frontline FCR therapy.ResultsThree months after the completion of therapy, 35% of patients had developed grade 2 to 4 cytopenia (according to Common Terminology Criteria for Adverse Events [version 4.0]). Factors found to be associated with cytopenia at 3 months after therapy were older age, advanced Rai stage disease, and lower baseline blood counts. Moreover, patients with cytopenia were less likely to have completed 6 courses of therapy with FCR. At 6 months and 9 months after therapy, the prevalence of grade 2 to 4 cytopenia was 24% and 12%, respectively. No differences in progression-free survival and overall survival were noted between cytopenic and noncytopenic patients or between patients with persistent and new-onset cytopenia. The prevalence of TRMM was 2.3% and did not differ significantly between cytopenic and noncytopenic patients or between those with persistent and new-onset disease. Late infections were more common in patients who were cytopenic at 9 months (38%) and were mostly bacterial (67%).ConclusionsCytopenia after the completion of therapy is a common complication of frontline FCR that improves over time, particularly for new-onset cases. The presence of persistent cytopenia (lasting up to 9 months after the completion of therapy) should not raise concern about CLL recurrence of the development of TRMM, but should encourage surveillance for bacterial infections for an additional 9 months.
- Published
- 2013
37. The synthetic heat shock protein 90 (Hsp90) inhibitor EC141 induces degradation of Bcr-Abl p190 protein and apoptosis of Ph-positive acute lymphoblastic leukemia cells
- Author
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Tong, Wei-Gang, Estrov, Zeev, Wang, Yongtao, O’Brien, Susan, Faderl, Stefan, Harris, David M., Van Pham, Quin, Hazan-Halevy, Inbal, Liu, Zhiming, Koch, Patricia, Kantarjian, Hagop, Keating, Michael J., and Ferrajoli, Alessandra
- Published
- 2011
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38. Mitoxantrone and high-dose cytosine arabinoside for the treatment of refractory acute lymphocytic leukemia
- Author
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Kantarjian, Hagop M., Walters, Ronald L., Keating, Michael J., Estey, Elihu H., O'Brien, Susan, Schachner, Jay, McCredie, Kenneth B., and Freireich, Emil J.
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Lymphocytic leukemia ,Mitoxantrone hydrochloride -- Evaluation ,Cytarabine -- Evaluation ,Leukemia ,Health - Abstract
Although great advances in the treatment of acute lymphocytic leukemia (ALL) have been made over the past two decades, its prognosis still depends strongly on several host and tumor attributes. Characteristics like patient age, degree of leukocytosis, and chromosome abnormalities of the tumor cells all influence the relative chances for long-term remission, which range from 40 to 50 percent in patients at average risk and less than 20 percent for patients with greater risk factors. Refractory ALL, which doesn't respond to conventional treatment, has been treated with high doses of cytosine arabinoside (ara-C), and response rates of between 20 and 60 percent have been reported. Likewise, mitoxantrone has been used in these patients and similar response rates have been found. Since the toxic effects of ara-C and mitoxantrone do not overlap, there is little reason not to try both drugs simultaneously, and there may, in fact, be some beneficial antileukemic effects as a result of combining them. To examine this combination of drugs, 25 patients with a diagnosis of refractory ALL were treated with 5mg per square meter (of body surface) mitoxantrone over one hour daily for five days, and 3mg ara-C over two hours every twelve hours for six doses. For purposes of this study, complete remission was defined on the basis of bone marrow examination. A percentage of blast cells, immature, undifferentiated cells, under 5 percent was regarded as complete remission (CR). Complete remission was observed in 9 of 25 patients (36 percent). Eight patients had disease which was resistant to this treatment, and another eight died during the treatment, primarily of complications induced by chemotherapy. The overall median survival time for the 25 patients was 10 weeks, while among the patients achieving remission, the median survival period was 16 weeks. Although the improvement in survival seems promising, the deaths due to the suppression of the bone marrow were higher than seen with some other treatments, suggesting that some sort of additional support for immune function be provided patients treated with mitoxantrone and high-dose cytosine arabinoside. (Consumer Summary produced by Reliance Medical Information, Inc.)
- Published
- 1990
39. The landscape of genetic mutations in patients with chronic lymphocytic leukaemia and complex karyotype.
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Strati, Paolo, Wang, Feng, Tambaro, Francesco P., Thompson, Philip A., Burger, Jan A., Jain, Nitin, Ferrajoli, Alessandra, Bose, Prithviraj, Estrov, Zeev, Keating, Michael J., Futreal, Andrew, Takahashi, Koichi, and Wierda, William G.
- Subjects
LEUKEMIA ,CHRONIC lymphocytic leukemia ,LYMPHOCYTOSIS - Abstract
Stimulated conventional metaphase karyotype (CMK) is a reliable method to identify complex karyotype (CK), which has been associated with an unfavourable prognosis in patients with chronic lymphocytic leukaemia (CLL) (Thompson et al, [10]). Patient baseline characteristics at time of gene mutation testing among 71 patients with CK and in a control group of 90 patients without CK, cared for during the same time range. When limiting the analysis to the 89 patients with treatment-naïve CLL, the 34 patients with CK (including high CK), had a significantly higher prevalence of mutated TP53 (29% vs. 7%, P = 0-008). When comparing the 43 patients with high CK to the 118 patients without high CK, only the association with mutated TP53 was maintained (42% vs. 13%, P < 0-001) (Fig A; Data S1). [Extracted from the article]
- Published
- 2019
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40. Mononuclear cell polyamine content associated with myeloid maturation in patients with leukemia during administration of polyamine inhibitors
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Maddox, Anne-Marie, Keating, Michael J., Freireich, Emil J., and Haddox, Mari K
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- 1989
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41. Alterations in human circulating and bone marrow mononuclear cell polyamine levels in hematologic malignancies as a consequence of difluoromethylornithine administration
- Author
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Maddox, Anne-Marie, Freireich, Emil J., Keating, Michael J., Frasier-Scott, Karen F., and Haddox, Mari K.
- Published
- 1988
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42. Leukemia and Cigarette Smoking
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Spitz, Margaret R., Fueger, John J., Newell, Guy R., and Keating, Michael J.
- Published
- 1990
43. Generation of Functional CLL-Specific Cord Blood CTL Using CD40-Ligated CLL APC.
- Author
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Decker, William K., Nina Shah, Dongxia Xing, Lapushin, Ruth, Sufang Li, Robinson, Simon N., Hong Yang, Parmar, Simrit, Halpert, Matthew M., Keating, Michael J., Gribben, John G., Molldrem, Jeffrey J., Shpall, Elizabeth J., and Wierda, William G.
- Subjects
CORD blood ,HLA histocompatibility antigens ,CELLS ,IMMUNITY ,SYNAPSES ,LEUKEMIA - Abstract
Though remissions have been observed following allo-HSCT for the treatment of CLL, many CLL patients are ineligible for transplant due to the lack of HLA-compatible donors. The use of umbilical cord blood (UCB) permits transplantation of many patients who lack HLA-compatible donors due to reduced requirements for stringent HLA matching between graft and recipient; however, disease relapse remains a concern with this modality. The generation of CLL-specific CTL from UCB T-cells, primed and expanded against the leukemic clone, might enhance the GVL effect and improve outcomes with UCB transplantation. Here we report the generation of functional, CLL-specific CTL using CD40-ligated CLL cells to prime partially-HLA matched UCB T-cells. Functionality and specificity were demonstrated by immune synapse assay, IFN-γ ELISpot, multi-parametric intracellular cytokine flow cytometry, and
51 Cr release assay. The use of patient-specific, non-CLL controls demonstrated the generation of both alloantigen and CLL-specific responses. Subsequently, we developed a clinically-applicable procedure permitting separation of alloreactive CTL from leukemia-specific CTL. Leukemia-specific CTL were able to mediate in vivo killing of CLL in humanized mice without concurrent or subsequent development of xenoGVHD. Our results demonstrate that generation of CLL-specific effectors from UCB is feasible and practical, and the results support further exploration of this strategy as a treatment modality for CLL. [ABSTRACT FROM AUTHOR]- Published
- 2012
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44. Stromal control of cystine metabolism promotes cancer cell survival in chronic lymphocytic leukaemia.
- Author
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Zhang, Wan, Trachootham, Dunyaporn, Liu, Jinyun, Chen, Gang, Pelicano, Helene, Garcia-Prieto, Celia, Lu, Weiqin, Burger, Jan A., Croce, Carlo M., Plunkett, William, Keating, Michael J., and Huang, Peng
- Subjects
MESENCHYMAL stem cells ,LEUKEMIA ,CHRONIC lymphocytic leukemia ,DRUG resistance ,GLUTATHIONE synthase ,CELL-mediated cytotoxicity ,GENE therapy ,CANCER risk factors - Abstract
Tissue stromal cells interact with leukaemia cells and profoundly affect their viability and drug sensitivity. Here we show a biochemical mechanism by which bone marrow stromal cells modulate the redox status of chronic lymphocytic leukaemia (CLL) cells and promote cellular survival and drug resistance. Primary CLL cells from patients exhibit a limited ability to transport cystine for glutathione (GSH) synthesis owing to a low expression level of Xc-transporter. In contrast, bone marrow stromal cells effectively import cystine and convert it to cysteine, which is then released into the microenvironment for uptake by CLL cells to promote GSH synthesis. The elevated level of GSH enhances leukaemia cell survival and protects them from drug-induced cytotoxicity. Furthermore, disabling this protective mechanism significantly sensitizes CLL cells to drug treatment in the stromal environment. This stromal-leukaemia interaction is critical for CLL cell survival and represents a key biochemical pathway for effectively targeting leukaemia cells to overcome drug resistance in vivo. [ABSTRACT FROM AUTHOR]
- Published
- 2012
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45. The B cell antigen receptor in atypical chronic lymphocytic leukemia with t(14;19)(q32;q13) demonstrates remarkable stereotypy.
- Author
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Schweighofer, Carmen D., Huh, Yang O., Luthra, Rajyalakshmi, Sargent, Rachel L., Ketterling, Rhett P., Knudson, Ryan A., Barron, Lynn L., Medeiros, L. Jeffrey, Keating, Michael J., and Abruzzo, Lynne V.
- Subjects
CHROMOSOMES ,B cells ,LEUKEMIA ,LYMPHOMAS ,ANTIGENS - Abstract
The article presents research on the role of t(14;19)(q32;q13) chromosomal translocation in B-cell leukemias and lymphomas. Chronic lymphocytic leukemia (CLL) cases associated with t(14;19) often exhibit morphologic and immunophenotypic features and unmutated immunoglobulin heavy chain (IGH) variable region (V) genes. An analysis of IGHV somatic mutation status and gene use in 11 patients with t(14;19)-positive CLL was conducted. A possibility exists that a specific antigen drive is involved in CLL formation.
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- 2011
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46. Treatment of Fludarabine-refractory Chronic Lymphocytic Leukemia.
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Tsimberidou, Apostolia-Maria and Keating, Michael J.
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- *
CHRONIC lymphocytic leukemia treatment , *STEM cell transplantation , *FLUDARABINE , *PURINE nucleotides , *LYMPHOCYTIC leukemia , *LEUKEMIA , *PROGNOSIS , *LEUKEMIA treatment , *THERAPEUTICS - Abstract
The article offers information on the treatment for fludarabine-refractory chronic lymphocytic leukemia (CLL). Cumulative evidence proposes that allogeneic stem cell transplantation is an effective therapeutic strategy for patients who are not responding to fludarabine. It states that chemoimmunotherapy regimen that includes rituximab or alemtuzuman and allogeneic stem cell transplantation ameliorate the prognosis of fludarabine-refractory CLL.
- Published
- 2009
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47. Graft- versus-leukaemia effect after non-myeloablative haematopoietic transplantation can overcome the unfavourable expression of ZAP-70 in refractory chronic lymphocytic leukaemia.
- Author
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Khouri, Issa F., Saliba, Rima M., Admirand, Joan, O'Brien, Susan, Lee, Ming-S., Korbling, Martin, Samuels, Barry I., Giralt, Sergio, Lima, de Marcos, Keating, Michael J., Champlin, Richard E., and Bueso-Ramos, Carlos
- Subjects
LEUKEMIA ,LYMPHOCYTES ,FLUDARABINE ,CANCER prognosis ,T cells - Abstract
ZAP-70 (zeta-chain-associated protein 70 kDa) expression is associated with poor prognosis in patients with chronic lymphocytic leukaemia (CLL). This study evaluated the efficacy of non-myeloablative allogeneic stem cell transplantation in patients with advanced CLL and assessed the impact of ZAP-70 expression on the outcome. Thirty-nine sequential patients were included. All had previously been treated with fludarabine. All patients received a preparative regimen of fludarabine (30 mg/m
2 /d for 3 d), intravenous cyclophosphamide (750 mg/m2 /d for 3 d), and high-dose rituximab. Immunohistochemical techniques on marrow biopsy samples were used to determine that ZAP-70 was expressed in 25 patients, whereas 13 other patients were ZAP-70 negative, and one was of indeterminate status. With a median follow-up time of 27 months, the estimated overall survival and current progression-free survival (CPFS) rates at 4 years were 48% and 44% respectively. Patients who were ZAP-70 positive had 56% survival, and their CPFS rate increased from 30% to 53% after a donor lymphocyte infusion. Multivariate analysis indicated that chemorefractory disease and mixed T cell chimerism at day 90, but not ZAP-70 positivity, were associated with the risk of disease progression after transplantation. These results demonstrate a potent graft- versus-leukaemia effect that can overcome the adverse prognostic effect of ZAP-70 expression. [ABSTRACT FROM AUTHOR]- Published
- 2007
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48. Immune anaemias in patients with chronic lymphocytic leukaemia treated with fludarabine, cyclophosphamide and rituximab – incidence and predictors.
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Borthakur, Gautam, O'Brien, Susan, Wierda, William G., Thomas, Deborah A., Cortes, Jorge E., Giles, Francis J., Kantarjian, Hagop M., Lerner, Susan, and Keating, Michael J.
- Subjects
ANEMIA ,BLOOD diseases ,LEUKEMIA ,CHRONIC diseases ,FLUDARABINE - Abstract
Immune anaemias (IA) [auto-immune haemolytic anaemia (AIHA) and pure red cell aplasia (PRCA)] are complications of chronic lymphocytic leukaemia (CLL). Fludarabine has been associated with AIHA, whereas both rituximab and cyclophosphamide have been used to treat this condition. Combining these agents with fludarabine may reduce the likelihood of AIHA. We report on the incidence, outcome and pretreatment predictors of IA in 300 patients treated with fludarabine, cyclophosphamide and rituximab (FCR). Nineteen patients (6·5%) developed IA [AIHA (5·8%), PRCA (0·7%)] on or after treatment with FCR. Most patients (82·4%) with AIHA had a negative direct antiglobulin test (DAT). Additional markers of haemolysis (indirect hyperbilirubinaemia, reticulocytosis, low haptoglobin and elevated lactate dehydrogenase levels) confirmed the presence of AIHA in these patients. The majority of patients responded to therapies including steroids, ciclosporin, i.v. immunoglobulin, etc. High pretreatment levels of beta-2 microglobulin predicted for development of IA. No haemolytic crisis was observed during FCR therapy in eight patients with AIHA prior to FCR. Thus, the incidence of IA among CLL patients treated with FCR was comparable with historical rates. The diagnosis of AIHA can be considered even if the DAT is negative. Pre-existing AIHA need not preclude front-line FCR therapy. [ABSTRACT FROM AUTHOR]
- Published
- 2007
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49. The t(14;19)(q32;q13)-positive small B-cell leukaemia: a clinicopathologic and cytogenetic study of seven cases.
- Author
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Huh, Yang O., Abruzzo, Lynne V., Rassidakis, George Z., Parry-Jones, Nilima, Schlette, Ellen, Brito-Bapabulle, Vasantha, Matutes, Estella, Wotherspoon, Andrew, Keating, Michael J., Medeiros, L. Jeffrey, and Catovsky, Daniel
- Subjects
LEUKEMIA ,B cells ,CYTOGENETICS ,PATHOLOGY ,LYMPHOCYTES - Abstract
The t(14;19)(q32;q13), involving the BCL3 locus at chromosome 19q13 and the immunoglobulin heavy chain gene at 14q32, is a rare recurrent cytogenetic abnormality identified in B-cell neoplasms, most of which have been classified as chronic lymphocytic leukaemia (CLL) in the literature. We describe the clinicopathological, immunophenotypic and cytogenetic findings in seven patients with B-cell neoplasms associated with t(14;19)(q32;q13). There were five men and two women, with a median age of 48 years (range 33–68). All had absolute lymphocytosis, six had lymphadenopathy, and one had splenomegaly. Lymphocytes in blood and bone marrow aspirate smears were predominantly small and cytologically atypical. Flow cytometric immunophenotyping showed an atypical immunophenotype with low CLL scores. The growth pattern in bone marrow biopsy specimens was interstitial to diffuse; immunohistochemical stains were positive for bcl3 and negative for cyclin D1. Lymph node biopsy specimens of two patients revealed total architectural effacement by neoplasm with proliferation centres. In addition to t(14;19), cytogenetic studies demonstrated trisomy 12 in five patients. These results suggest that B-cell neoplasms with the t(14;19)(q32;q13) present frequently as leukaemia composed of small B-lymphocytes and share many features with CLL. However, these neoplasms also differ from CLL cytologically and in their immunophenotype. [ABSTRACT FROM AUTHOR]
- Published
- 2007
- Full Text
- View/download PDF
50. Epstein-Barr virus in patients with chronic lymphocytic leukemia: A pilot study.
- Author
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Tsimberidou, Apostolia-Maria, Keating, Michael J., Bueso-Ramos, Carlos E., and Kurzrock, Razelle
- Subjects
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EPSTEIN-Barr virus , *CHRONIC lymphocytic leukemia , *LYMPHOCYTIC leukemia , *LYMPHOMAS , *HEMATOLOGICAL oncology - Abstract
The objective of this study was to assess the incidence and the clinical significance of Epstein-Barr virus (EBV) in patients with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL). Patients with CLL/SLL who presented at The University of Texas M. D. Anderson Cancer Center over a 2-year period and had available marrow paraffin blocks were studied for evidence of EBV infection using a highly specific in-situ hybridization assay for detection of EBV encoded RNA (EBERs). Results were analysed in relation to other presenting characteristics and outcome. Thirty-two patients were examined. EBERs were detected in the bone marrow of 12 of 32 (38%) CLL/SLL marrows vs 0 of 20 normal marrows ( p = 0.002). EBERs were observed in sporadic granulocytes alone or in addition to its presence in lymphocytes in nine of the 12 EBV-positive patients. EBERs were detected less frequently in patients with Rai stage 0 – 1 disease (20%) compared with Rai stage 2 – 4 (66%; p = 0.008). EBER-positive patients tended to have higher lactate dehydrogenase levels ( p = 0.053). The 10-year survival rate was 22% vs 58% for patients with and without discernible EBERs (log-rank, p = 0.08). Evidence of EBV infection was found in 38% of patients with CLL/SLL. Despite the small number of patients tested, discernable EBERs were significantly more common in individuals with more advanced Rai stage and there was a trend toward shorter survival in patients in whom EBV EBERs were discerned. Larger studies are needed to determine the prognostic value and role of EBV infection in patients with CLL/SLL. [ABSTRACT FROM AUTHOR]
- Published
- 2006
- Full Text
- View/download PDF
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