2,665 results on '"Keating, Michael J."'
Search Results
2. A phase two study of high dose blinatumomab in Richter’s syndrome
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Thompson, Philip A., Jiang, Xianli, Banerjee, Pinaki, Basar, Rafet, Garg, Naveen, Chen, Ken, Kaplan, Mecit, Nandivada, Vandana, Cortes, Ana Karen Nunez, Ferrajoli, Alessandra, Keating, Michael J., Peterson, Christine B., Andreeff, Michael, Rezvani, Katayoun, and Wierda, William G.
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- 2022
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3. Topological Structures in the Space of Treatment-Naive Patients With Chronic Lymphocytic Leukemia
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McGee, Reginald L., primary, Reed, Jake, additional, Coombes, Caitlin E., additional, Herling, Carmen D., additional, Keating, Michael J., additional, Abruzzo, Lynne V., additional, and Coombes, Kevin R., additional
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- 2024
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4. Cyclin-dependent kinase inhibitor fadraciclib (CYC065) depletes anti-apoptotic protein and synergizes with venetoclax in primary chronic lymphocytic leukemia cells
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Chen, Rong, Chen, Yuling, Xiong, Ping, Zheleva, Daniella, Blake, David, Keating, Michael J., Wierda, William G., and Plunkett, William
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- 2022
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5. 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
6. 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).
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- 2019
7. 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
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- 2018
8. Topological Structures in the Space of Treatment-Naïve Patients with Chronic Lymphocytic Leukemia.
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McGee II, Reginald L., Reed, Jake, Coombes, Caitlin E., Herling, Carmen D., Keating, Michael J., Abruzzo, Lynne V., and Coombes, Kevin R.
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CHRONIC lymphocytic leukemia ,STATISTICAL models ,COMPUTER-assisted image analysis (Medicine) ,RESEARCH funding ,CANCER patients ,TECHNOLOGY ,DIGITAL image processing ,GENETIC mutation - Abstract
Simple Summary: Clinical data sets incorporate continuous data like blood pressure or sodium levels, categorical data like cancer grade or stage, and binary data like sex or marital status. Measurements on an individual patient define a point in a high-dimensional space; data from many patients defines a "point cloud". The "shape" of the point cloud influences experimental design by describing patient variability. Topological data analysis (TDA) is a mathematical technique for understanding the shape of point clouds by finding "holes" that correspond to combinations of patient characteristics that are never observed. TDA results are stratified by dimension. Zero-dimensional features define patient subtypes. One-dimensional features ("loops") are analogs of the inside of a circle or a donut hole. Two-dimensional features ("voids") are analogs of the inside of a balloon. Here, we apply TDA to a clinical data set of previously untreated patients with Chronic Lymphocytic Leukemia to find loops and voids. Patients are complex and heterogeneous; clinical data sets are complicated by noise, missing data, and the presence of mixed-type data. Using such data sets requires understanding the high-dimensional "space of patients", composed of all measurements that define all relevant phenotypes. The current state-of-the-art merely defines spatial groupings of patients using cluster analyses. Our goal is to apply topological data analysis (TDA), a new unsupervised technique, to obtain a more complete understanding of patient space. We applied TDA to a space of 266 previously untreated patients with Chronic Lymphocytic Leukemia (CLL), using the "daisy" metric to compute distances between clinical records. We found clear evidence for both loops and voids in the CLL data. To interpret these structures, we developed novel computational and graphical methods. The most persistent loop and the most persistent void can be explained using three dichotomized, prognostically important factors in CLL: IGHV somatic mutation status, beta-2 microglobulin, and Rai stage. In conclusion, patient space turns out to be richer and more complex than current models suggest. TDA could become a powerful tool in a researcher's arsenal for interpreting high-dimensional data by providing novel insights into biological processes and improving our understanding of clinical and biological data sets. [ABSTRACT FROM AUTHOR]
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- 2024
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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. Clinical Trials with Nucleoside Analogs in Other Hematologic Malignancies
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Cortes, Jorge E., primary, Kantarjian, Hagop, additional, O’Brien, Susan M., additional, and Keating, Michael J., additional
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- 2021
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13. Nucleoside Analogs in Cancer Therapy
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Cheson, Bruce D., primary, Keating, Michael J., additional, and Plunkett, William, additional
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- 2021
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14. Clinical Trials of the Purine Analogs in Chronic Lymphocytic Leukemia
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Keating, Michael J., primary
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- 2021
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15. 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.
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- 2017
16. 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
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- 2017
17. 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.
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- 2017
18. 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 (
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- 2017
19. 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.
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- 2017
20. 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
21. 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
22. CXCL13 plasma levels function as a biomarker for disease activity in patients with chronic lymphocytic leukemia
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Sivina, Mariela, Xiao, Lianchun, Kim, Ekaterina, Vaca, Alicia, Chen, Shih-Shih, Keating, Michael J., Ferrajoli, Alessandra, Estrov, Zeev, Jain, Nitin, Wierda, William G., Huang, Xuelin, Chiorazzi, Nicholas, and Burger, Jan A.
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- 2021
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23. Ofatumumab is safe and effective as front-line treatment in older patients with chronic lymphocytic leukemia and severe co-morbidities, including other malignancies
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Vitale, Candida, Falchi, Lorenzo, Ciccone, Maria, Burger, Jan, Pemmaraju, Naveen, Borthakur, Gautam, Wierda, William G., Keating, Michael J., and Ferrajoli, Alessandra
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- 2020
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24. 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
25. 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
26. 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
27. 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
28. 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.
- Published
- 2016
29. 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
- Subjects
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
30. Sustained remissions in CLL after frontline FCR treatment with very-long-term follow-up
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Thompson, Philip A., primary, Bazinet, Alexandre, additional, Wierda, William G., additional, Tam, Constantine S., additional, O’Brien, Susan M., additional, Saha, Satabdi, additional, Peterson, Christine B., additional, Plunkett, William, additional, and Keating, Michael J., additional
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- 2023
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31. CCL3 and CCL4 are biomarkers for B cell receptor pathway activation and prognostic serum markers in diffuse large B cell lymphoma
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Takahashi, Koichi, Sivina, Mariela, Hoellenriegel, Julia, Oki, Yasuhiro, Hagemeister, Fredrick B, Fayad, Luis, Romaguera, Jorge E, Fowler, Nathan, Fanale, Michelle A, Kwak, Larry W, Samaniego, Felipe, Neelapu, Sattva, Xiao, Lianchun, Huang, Xuelin, Kantarjian, Hagop, Keating, Michael J, Wierda, William, Fu, Kai, Chan, Wing C, Vose, Julie M, O'Brien, Susan, Davis, Richard E, and Burger, Jan A
- Subjects
Biomedical and Clinical Sciences ,Cardiovascular Medicine and Haematology ,Oncology and Carcinogenesis ,Cancer ,Rare Diseases ,Lymphoma ,Hematology ,Clinical Research ,Aetiology ,2.1 Biological and endogenous factors ,Adenine ,Antineoplastic Agents ,B-Cell Activation Factor Receptor ,Biomarkers ,Tumor ,Cell Line ,Tumor ,Chemokine CCL3 ,Chemokine CCL4 ,Enzyme-Linked Immunosorbent Assay ,Epidemiologic Methods ,Humans ,Lymphoma ,Large B-Cell ,Diffuse ,Piperidines ,Prognosis ,Pyrazoles ,Pyrimidines ,Signal Transduction ,chemokines ,diffuse large B-cell lymphoma ,lymphoma ,Cardiorespiratory Medicine and Haematology ,Immunology ,Cardiovascular medicine and haematology - Abstract
B cell receptor (BCR) signalling is an important pathway in diffuse large B cell lymphoma (DLBCL). In response to BCR triggering, normal and malignant B cells secrete the chemokines CCL3 and CCL4 to attract accessory cells to the tissue microenvironment. We measured CCL3 and CCL4 serum concentrations in 102 patients with newly diagnosed DLBCL by enzyme-linked immunosorbent assay, investigated their prognostic impact and validated our findings in an independent cohort of 51 patient samples. We also tested CCL3 and CCL4 secretion by DLBCL cells, and the influence of BTK inhibitors on the secretion of these chemokines. High CCL3 (≥40 pg/ml) serum concentrations correlated with higher international prognostic index, lactate dehydrogenase and β2 microglobulin, as did CCL4 (≥180 pg/ml) with advanced Ann Arbor stages. High CCL3 levels correlated with significantly shorter progression-free and overall survival. The in vitro studies demonstrated that activated B cell-like, but not germinal centre B cell-like DLBCL cells, secrete high levels of CCL3 and CCL4 after BCR triggering, which was exquisitely sensitive to BCR pathway inhibition. These findings support CCL3 and CCL4 protein concentrations as biomarkers for BCR pathway activation and prognosis in DLBCL.
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- 2015
32. 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
- Subjects
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
33. 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
34. 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
35. Management of adverse events associated with idelalisib treatment: expert panel opinion
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Coutré, Steven E, Barrientos, Jacqueline C, Brown, Jennifer R, de Vos, Sven, Furman, Richard R, Keating, Michael J, Li, Daniel, O’Brien, Susan M, Pagel, John M, Poleski, Martin H, Sharman, Jeff P, Yao, Nai-Shun, and Zelenetz, Andrew D
- Subjects
Biomedical and Clinical Sciences ,Clinical Sciences ,Cancer ,Patient Safety ,Digestive Diseases ,Development of treatments and therapeutic interventions ,Evaluation of treatments and therapeutic interventions ,6.1 Pharmaceuticals ,5.1 Pharmaceuticals ,Good Health and Well Being ,Algorithms ,Antineoplastic Agents ,Class Ia Phosphatidylinositol 3-Kinase ,Diet Therapy ,Disease Management ,Drug-Related Side Effects and Adverse Reactions ,Enzyme Inhibitors ,Expert Testimony ,Hematologic Neoplasms ,Humans ,Phosphatidylinositol 3-Kinases ,Phosphoinositide-3 Kinase Inhibitors ,Proto-Oncogene Proteins c-akt ,Purines ,Quinazolinones ,Signal Transduction ,TOR Serine-Threonine Kinases ,Treatment Outcome ,Idelalisib ,phosphatidylinositol 3-kinase delta (PI3K) inhibitor ,diarrhea ,colitis ,transaminitis ,pneumonitis ,phosphatidylinositol 3-kinase delta (PI3Kδ) inhibitor ,Immunology ,Cardiovascular medicine and haematology - Abstract
Idelalisib is a first-in-class selective, oral, phosphatidylinositol 3-kinase delta (PI3Kδ) inhibitor approved for the treatment of several types of blood cancer. Idelalisib has demonstrated significant efficacy and a tolerable safety profile in clinical trials. However, the US prescribing information contains a black box warning for fatal and/or severe diarrhea or colitis, hepatotoxicity, pneumonitis and intestinal perforation. An expert panel was convened to review the pathology of these treatment-emergent adverse events (TEAEs) to propose key management tools for patients receiving idelalisib therapy. This article provides an overview of idelalisib TEAEs reported in clinical trials, and a summary of the panel's recommendations for identification and management of idelalisib treatment-emergent diarrhea or colitis as well as a discussion of transaminitis and pneumonitis. For idelalisib-related diarrhea or colitis (including unresolved grade 2 and grade ≥ 3), after exclusion of infectious causes, the panel recommends individualized treatment with budesonide or oral or intravenous steroid therapy.
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- 2015
36. Minimal residual disease undetectable by next-generation sequencing predicts improved outcome in CLL after chemoimmunotherapy
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Thompson, Philip A., Srivastava, Jaya, Peterson, Christine, Strati, Paolo, Jorgensen, Jeffrey L., Hether, Tyler, Keating, Michael J., O'Brien, Susan M., Ferrajoli, Alessandra, Burger, Jan A., Estrov, Zeev, Jain, Nitin, and Wierda, William G.
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- 2019
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37. Time-to-progression after front-line fludarabine, cyclophosphamide, and rituximab chemoimmunotherapy for chronic lymphocytic leukaemia: a retrospective, multicohort study
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Herling, Carmen D, Coombes, Kevin R, Benner, Axel, Bloehdorn, Johannes, Barron, Lynn L, Abrams, Zachary B, Majewski, Tadeusz, Bondaruk, Jolanta E, Bahlo, Jasmin, Fischer, Kirsten, Hallek, Michael, Stilgenbauer, Stephan, Czerniak, Bogdan A, Oakes, Christopher C, Ferrajoli, Alessandra, Keating, Michael J, and Abruzzo, Lynne V
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- 2019
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38. The BET inhibitor GS-5829 targets chronic lymphocytic leukemia cells and their supportive microenvironment
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Kim, Ekaterina, ten Hacken, Elisa, Sivina, Mariela, Clarke, Astrid, Thompson, Philip A., Jain, Nitin, Ferrajoli, Alessandra, Estrov, Zeev, Keating, Michael J., Wierda, William G., Bhalla, Kapil N., and Burger, Jan A.
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- 2020
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39. 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
40. 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
41. 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
42. 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.
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- 2015
43. 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
44. Randomized trial of ibrutinib vs ibrutinib plus rituximab in patients with chronic lymphocytic leukemia
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Burger, Jan A., Sivina, Mariela, Jain, Nitin, Kim, Ekaterina, Kadia, Tapan, Estrov, Zeev, Nogueras-Gonzalez, Graciela M., Huang, Xuelin, Jorgensen, Jeffrey, Li, Jianling, Cheng, Mei, Clow, Fong, Ohanian, Maro, Andreeff, Michael, Mathew, Thomas, Thompson, Philip, Kantarjian, Hagop, O'Brien, Susan, Wierda, William G., Ferrajoli, Alessandra, and Keating, Michael J.
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- 2019
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45. 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
46. 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.
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- 2014
47. A pilot study of lower doses of ibrutinib in patients with chronic lymphocytic leukemia
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Chen, Lisa S., Bose, Prithviraj, Cruz, Nichole D., Jiang, Yongying, Wu, Qi, Thompson, Philip A., Feng, Shuju, Kroll, Michael H., Qiao, Wei, Huang, Xuelin, Jain, Nitin, Wierda, William G., Keating, Michael J., and Gandhi, Varsha
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- 2018
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48. 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.
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- 2014
49. Global miRNA profiling reveals key molecules that contribute to different chronic lymphocytic leukemia incidences in Asian and Western populations
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Liu, Panpan, primary, Wang, Kefeng, additional, Li, Jianan, additional, Ogasawara, Marcia A., additional, Xia, Zhongjun, additional, Wierda, William G., additional, Keating, Michael J., additional, Li, Yiqing, additional, and Huang, Peng, additional
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- 2023
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50. 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
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