96 results on '"Keating, Michael J."'
Search Results
2. Sustained remissions in CLL after frontline FCR treatment with very-long-term follow-up.
- Author
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Thompson PA, Bazinet A, Wierda WG, Tam CS, O'Brien SM, Saha S, Peterson CB, Plunkett W, and Keating MJ
- Subjects
- Humans, Rituximab, Follow-Up Studies, Treatment Outcome, Antineoplastic Combined Chemotherapy Protocols adverse effects, Cyclophosphamide, Vidarabine, Leukemia, Lymphocytic, Chronic, B-Cell genetics
- Abstract
Chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab (FCR) achieves durable remissions, with flattening of the progression-free survival (PFS) curve in patients with mutated immunoglobulin heavy chain variable gene (IGHV-M). We updated long-term follow-up results from the original 300-patient FCR study initiated at MD Anderson in 1999. The current median follow-up is 19.0 years. With this extended follow-up, the median PFS for patients with IGHV-M was 14.6 years vs 4.2 years for patients with unmutated IGHV (IGHV-UM). Disease progression beyond 10 years was uncommon. In total, 16 of 94 (17%) patients in remission at 10 years subsequently progressed with the additional follow-up compared with the patients in our prior report in 2015. Only 4 of 45 patients (9%) with IGHV-M progressed beyond 10 years. Excluding Richter transformation, 96 of 300 patients (32%) developed 106 other malignancies, with 19 of 300 (6.3%) developing therapy-related myeloid neoplasms (tMNs), which were fatal in 16 of 19 (84%). No pretreatment patient characteristics predicted the risk of tMNs. In summary, FCR remains an option for patients with IGHV-M chronic lymphocytic leukemia (CLL), with a significant fraction achieving functional cure of CLL. A risk-benefit assessment is warranted when counseling patients, balancing potential functional cure with the risk of late relapses and serious secondary malignancies., (© 2023 by The American Society of Hematology.)
- Published
- 2023
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3. Achieving complete remission in CLL patients treated with ibrutinib: clinical significance and predictive factors.
- Author
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Strati P, Schlette EJ, Solis Soto LM, Duenas DE, Sivina M, Kim E, Keating MJ, Wierda WG, Ferrajoli A, Kantarjian H, Estrov Z, Jain N, Thompson PA, Wistuba II, and Burger JA
- Subjects
- Adenine analogs & derivatives, Aged, Female, Humans, Leukemia, Lymphocytic, Chronic, B-Cell immunology, Macrophages pathology, Male, Middle Aged, Phenotype, Piperidines, Remission Induction, Treatment Outcome, Leukemia, Lymphocytic, Chronic, B-Cell drug therapy, Pyrazoles therapeutic use, Pyrimidines therapeutic use
- Published
- 2020
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4. Ofatumumab is safe and effective as front-line treatment in older patients with chronic lymphocytic leukemia and severe co-morbidities, including other malignancies.
- Author
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Vitale C, Falchi L, Ciccone M, Burger J, Pemmaraju N, Borthakur G, Wierda WG, Keating MJ, and Ferrajoli A
- Subjects
- Aged, Antibodies, Monoclonal, Humanized, Comorbidity, Humans, Morbidity, Treatment Outcome, Leukemia, Lymphocytic, Chronic, B-Cell drug therapy
- Abstract
Background: The majority of patients with chronic lymphocytic leukemia (CLL) are older and have multiple comorbidities, including other cancer diagnoses. These patients are routinely excluded from participation in clinical trials., Objective: In this phase II study, we determined the activity and toxicity of ofatumumab, a fully human anti-CD20 monoclonal antibody, in older patients with CLL, poor performance status and comorbidities., Methods: Treatment-naïve patients with CLL aged ≥65 years with an ECOG performance status of 2-3 or Charlson comorbidity index ≥2 were eligible. Ofatumumab was administered intravenously weekly for the first month, then monthly for a total of 12 months., Results: Thirty-four patients were enrolled. Median age was 73 years, and 29% had another cancer diagnosis. Among 32 patients evaluable for response, the overall response rate was 72%. We observed complete responses in 19% of patients and partial responses in 53%. The median progression-free survival duration was 21 months, and the estimated proportion of patients alive at 36 months was 87%. All 34 patients were evaluable for toxicity. Treatment was well tolerated, with infusion-related reactions being the most common treatment-related adverse event. Only one patient had a grade 3 infection. Additional grade 3 adverse events that may have been related to ofatumumab were diarrhea, nausea/vomiting, hyperglycemia, pulmonary embolism, and hypersensitivity reaction, each in one patient. No grade 4 adverse events were observed., Conclusion: Single-agent ofatumumab is a well-tolerated and effective therapeutic approach for treatment-naïve older patients with CLL; it can be safely administered to patients with significant comorbidities and other cancer diagnoses., (Published by Elsevier Ltd.)
- Published
- 2020
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5. Minimal residual disease undetectable by next-generation sequencing predicts improved outcome in CLL after chemoimmunotherapy.
- Author
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Thompson PA, Srivastava J, Peterson C, Strati P, Jorgensen JL, Hether T, Keating MJ, O'Brien SM, Ferrajoli A, Burger JA, Estrov Z, Jain N, and Wierda WG
- Subjects
- Aged, Cyclophosphamide administration & dosage, Female, Follow-Up Studies, Humans, Male, Middle Aged, Neoplasm, Residual, Predictive Value of Tests, Rituximab administration & dosage, Vidarabine administration & dosage, Vidarabine analogs & derivatives, Antineoplastic Combined Chemotherapy Protocols administration & dosage, Flow Cytometry, High-Throughput Nucleotide Sequencing, Immunotherapy, Leukemia, Lymphocytic, Chronic, B-Cell blood, Leukemia, Lymphocytic, Chronic, B-Cell genetics, Leukemia, Lymphocytic, Chronic, B-Cell mortality, Leukemia, Lymphocytic, Chronic, B-Cell therapy
- Abstract
Patients with chronic lymphocytic leukemia (CLL) who achieve blood or bone marrow (BM) undetectable minimal residual disease (U-MRD) status after first-line fludarabine, cyclophosphamide, and rituximab (FCR) have prolonged progression-free survival (PFS), when assessed by an assay with sensitivity 10-4 (MRD4). Despite reaching U-MRD4, many patients, especially those with unmutated IGHV, subsequently relapse, suggesting residual disease <10-4 threshold and the need for more sensitive MRD evaluation. MRD evaluation by next-generation sequencing (NGS) has a sensitivity of 10-6 (MRD6). To better assess the depth of remission following first-line FCR treatment, we used NGS (Adaptive Biotechnologies Corporation) to assess MRD in 62 patients, all of whom had BM U-MRD by multicolor flow cytometry (sensitivity 10-4) at end-of-FCR treatment. Samples from these patients included 57 BM samples, 29 peripheral blood mononuclear cell (PBMC) samples, and 32 plasma samples. Only 27.4% of the 62 patients had U-MRD by NGS. Rate of U-MRD by NGS was lowest in BM (25%), compared with PBMC (55%) or plasma (75%). No patient with U-MRD by NGS in BM or PBMC was MRD+ in plasma. Patients with mutated IGHV were more likely to have U-MRD by NGS at the end of treatment (EOT; 41% vs 13%, P = .02) than those with unmutated IGHV. Median follow-up was 81.6 months. Patients with U-MRD at EOT had superior PFS vs MRD+ patients, regardless of sample type assessed (BM, P = .02, median not reached [NR] vs 67 months; PBMC, P = .02, median NR vs 74 months). More sensitive MRD6 testing increases prognostic discrimination over MRD4 testing., (© 2019 by The American Society of Hematology.)
- Published
- 2019
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6. Randomized trial of ibrutinib vs ibrutinib plus rituximab in patients with chronic lymphocytic leukemia.
- Author
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Burger JA, Sivina M, Jain N, Kim E, Kadia T, Estrov Z, Nogueras-Gonzalez GM, Huang X, Jorgensen J, Li J, Cheng M, Clow F, Ohanian M, Andreeff M, Mathew T, Thompson P, Kantarjian H, O'Brien S, Wierda WG, Ferrajoli A, and Keating MJ
- Subjects
- Adenine analogs & derivatives, Adult, Aged, Aged, 80 and over, Antineoplastic Combined Chemotherapy Protocols administration & dosage, Disease Progression, Disease-Free Survival, Drug Administration Schedule, Female, Humans, Kaplan-Meier Estimate, Male, Middle Aged, Neoplasm, Residual, Piperidines, Remission Induction, Treatment Outcome, Antineoplastic Agents, Immunological administration & dosage, Leukemia, Lymphocytic, Chronic, B-Cell drug therapy, Pyrazoles administration & dosage, Pyrimidines administration & dosage, Rituximab administration & dosage
- Abstract
Ibrutinib, an oral covalent inhibitor of Bruton's tyrosine kinase, is an effective therapy for patients with chronic lymphocytic leukemia (CLL). To determine whether rituximab provides added benefit to ibrutinib, we conducted a randomized single-center trial of ibrutinib vs ibrutinib plus rituximab. Patients with CLL requiring therapy were randomized to receive 28-day cycles of once-daily ibrutinib 420 mg, either as a single agent (n = 104), or together with rituximab (375 mg/m
2 ; n = 104), given weekly during cycle 1, then once per cycle until cycle 6. The primary end point was progression-free survival (PFS) in the intention-to-treat population. We enrolled 208 patients with CLL, 181 with relapsed CLL and 27 treatment-naive patients with high-risk disease (17p deletion or TP53 mutation). After a median follow-up of 36 months, the Kaplan-Meier estimates of PFS were 86% (95% confidence interval [CI], 76.6-91.9) for patients receiving ibrutinib, and 86.9% (95% CI, 77.3-92.6) for patients receiving ibrutinib plus rituximab. Similarly, response rates were the same in both arms (overall response rate, 92%). However, time to normalization of peripheral blood lymphocyte counts and time to complete remission were shorter, and residual disease levels in the bone marrow were lower, in patients receiving ibrutinib plus rituximab. We conclude that the addition of rituximab to ibrutinib in relapsed and treatment-naive high-risk patients with CLL failed to show improvement in PFS. However, patients treated with ibrutinib plus rituximab reached their remissions faster and achieved significantly lower residual disease levels. Given these results, ibrutinib as single-agent therapy remains current standard-of-care treatment in CLL. This trial was registered at www.clinicaltrials.gov as #NCT02007044., (© 2019 by The American Society of Hematology.)- Published
- 2019
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7. A pilot study of lower doses of ibrutinib in patients with chronic lymphocytic leukemia.
- Author
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Chen LS, Bose P, Cruz ND, Jiang Y, Wu Q, Thompson PA, Feng S, Kroll MH, Qiao W, Huang X, Jain N, Wierda WG, Keating MJ, and Gandhi V
- Subjects
- Adenine analogs & derivatives, Agammaglobulinaemia Tyrosine Kinase metabolism, Aged, Dose-Response Relationship, Drug, Female, Humans, Leukemia, Lymphocytic, Chronic, B-Cell metabolism, Male, Middle Aged, Pilot Projects, Piperidines, Protein Kinase Inhibitors administration & dosage, Pyrazoles administration & dosage, Pyrimidines administration & dosage, Signal Transduction drug effects, Treatment Outcome, Agammaglobulinaemia Tyrosine Kinase antagonists & inhibitors, Leukemia, Lymphocytic, Chronic, B-Cell drug therapy, Protein Kinase Inhibitors therapeutic use, Pyrazoles therapeutic use, Pyrimidines therapeutic use
- Abstract
Ibrutinib is highly efficacious and used at 420 mg/d for treatment of chronic lymphocytic leukemia (CLL). We previously demonstrated a decline in Bruton's tyrosine kinase (BTK) protein levels in CLL cells after 1 cycle of ibrutinib, suggesting ibrutinib dose could be lowered after the first cycle without loss of biological effect. To test this postulate, a pilot study (NCT02801578) was designed to systematically reduce ibrutinib dosing within the same patient with CLL over the course of three 28-day cycles. After an initial cycle of 420 mg/d, the dose was reduced to 280 mg/d in cycle 2, and then to 140 mg/d in cycle 3. Eleven patients began study treatment, and 9 completed the 3 cycles. Plasma and intracellular pharmacokinetics (PK), BTK occupancy, and pharmacodynamic (PD) response at different doses of ibrutinib were compared. Plasma and intracellular levels of ibrutinib were dose-dependent, and even the lowest dose was sufficient to occupy, on average, more than 95% of BTK protein. In concert, BTK downstream signaling inhibition was maintained with 140 mg/d ibrutinib in cycle 3, and there were comparable reductions in total and phospho-BTK (Tyr223) protein levels across 3 cycles. Reductions of plasma chemokine CCL3 and CCL4 levels, considered to be biomarkers of ibrutinib response, were similar during the 3 cycles. These PK/PD data demonstrate that after 1 cycle of ibrutinib at the standard 420 mg/d dose, the dose can be reduced without losing biological activity. Clinical efficacy of lower doses needs to be systematically evaluated. Such dose reductions would lower drug cost, lessen untoward toxicity, and facilitate rationale-based combinations. This trial was registered at www.clinicaltrials.gov as #NCT02801578., (© 2018 by The American Society of Hematology.)
- Published
- 2018
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8. The Stromal Microenvironment Modulates Mitochondrial Oxidative Phosphorylation in Chronic Lymphocytic Leukemia Cells.
- Author
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Vangapandu HV, Ayres ML, Bristow CA, Wierda WG, Keating MJ, Balakrishnan K, Stellrecht CM, and Gandhi V
- Subjects
- Apoptosis, Cell Communication, Cell Line, Tumor, Cell Survival, Glycolysis, Humans, Intracellular Space metabolism, Leukemia, Lymphocytic, Chronic, B-Cell genetics, Metabolic Networks and Pathways, Ribonucleotides metabolism, Tumor Cells, Cultured, Leukemia, Lymphocytic, Chronic, B-Cell metabolism, Leukemia, Lymphocytic, Chronic, B-Cell pathology, Mitochondria metabolism, Oxidative Phosphorylation, Stromal Cells metabolism, Tumor Microenvironment
- Abstract
Peripheral blood chronic lymphocytic leukemia (CLL) cells are replicationally quiescent mature B-cells. In short-term cultures, supporting stromal cells provide a survival advantage to CLL cells by inducing transcription and translation without promoting proliferation. We hypothesized that the stromal microenvironment augments malignant B cells' metabolism to enable the cells to cope with their energy demands for transcription and translation. We used extracellular flux analysis to assess the two major energy-generating pathways, mitochondrial oxidative phosphorylation (OxPhos) and glycolysis, in primary CLL cells in the presence of three different stromal cell lines. OxPhos, measured as the basal oxygen consumption rate (OCR) and maximum respiration capacity, was significantly higher in 28 patients' CLL cells cocultured with bone marrow-derived NK.Tert stromal cells than in CLL cells cultured alone (P = .004 and <.0001, respectively). Similar OCR induction was observed in CLL cells cocultured with M2-10B4 and HS-5 stromal lines. In contrast, heterogeneous changes in the extracellular acidification rate (a measure of glycolysis) were observed in CLL cells cocultured with stromal cells. Ingenuity Pathway Analysis of CLL cells' metabolomics profile indicated stroma-mediated stimulation of nucleotide synthesis. Quantitation of ribonucleotide pools showed a significant two-fold increase in CLL cells cocultured with stromal cells, indicating that the stroma may induce CLL cellular bioenergy and the RNA building blocks necessary for the transcriptional requirement of a prosurvival phenotype. The stroma did not impact the proliferation index (Ki-67 staining) of CLL cells. Collectively, these data suggest that short-term interaction (≤24 hours) with stroma increases OxPhos and bioenergy in replicationally quiescent CLL cells., (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2017
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9. Ibrutinib efficacy and tolerability in patients with relapsed chronic lymphocytic leukemia following allogeneic HCT.
- Author
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Ryan CE, Sahaf B, Logan AC, O'Brien S, Byrd JC, Hillmen P, Brown JR, Dyer MJ, Mato AR, Keating MJ, Jaglowski S, Clow F, Rezvani AR, Styles L, Coutre SE, and Miklos DB
- Subjects
- Adenine analogs & derivatives, Adult, Aged, B-Lymphocytes drug effects, B-Lymphocytes pathology, Chimerism, Cohort Studies, Female, Germinal Center pathology, Graft vs Host Disease etiology, Humans, Immunomodulation, Lymph Nodes pathology, Lymphocyte Depletion, Male, Middle Aged, Neoplasm, Residual pathology, Piperidines, Pyrazoles pharmacology, Pyrimidines pharmacology, Recurrence, Th2 Cells drug effects, Th2 Cells immunology, Tissue Donors, Transplantation, Homologous adverse effects, Treatment Outcome, Withholding Treatment, Hematopoietic Stem Cell Transplantation adverse effects, Leukemia, Lymphocytic, Chronic, B-Cell drug therapy, Leukemia, Lymphocytic, Chronic, B-Cell therapy, Pyrazoles adverse effects, Pyrazoles therapeutic use, Pyrimidines adverse effects, Pyrimidines therapeutic use
- Abstract
Ibrutinib, a potent and irreversible small-molecule inhibitor of both Bruton's tyrosine kinase and interleukin-2 inducible kinase (ITK), has been used to treat relapsed/refractory chronic lymphocytic leukemia (CLL) with prolongation of progression-free and overall survival. Here, we present 27 patients with relapsed CLL following allogeneic hematopoietic cell transplant (HCT) who subsequently received ibrutinib salvage therapy. Sixteen of these patients were part of multi-institutional clinical trials and achieved an overall response rate of 87.5%. An additional 11 patients were treated at Stanford University following US Food and Drug Administration approval of ibrutinib; 7 (64%) achieved a complete response, and 3 (27%) achieved a partial response. Of the 9 patients treated at Stanford who had mixed chimerism-associated CLL relapse, 4 (44%) converted to full donor chimerism following ibrutinib initiation, in association with disease response. Four of 11 (36%) patients evaluated by ClonoSeq achieved minimal residual disease negativity with CLL <1/10 000 white blood cells, which persisted even after ibrutinib was discontinued, in 1 case even after 26 months. None of the 27 patients developed graft-versus-host-disease (GVHD) following ibrutinib initiation. We postulate that ibrutinib augments the graft-versus-leukemia (GVL) benefit through a T-cell-mediated effect, most likely due to ITK inhibition. To investigate the immune modulatory effects of ibrutinib, we completed comprehensive immune phenotype characterization of peripheral B and T cells from treated patients. Our results show that ibrutinib selectively targets pre-germinal B cells and depletes Th2 helper cells. Furthermore, these effects persisted after drug discontinuation. In total, our results provide evidence that ibrutinib effectively augments GVL without causing GVHD., (© 2016 by The American Society of Hematology.)
- Published
- 2016
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10. Fludarabine, cyclophosphamide, and rituximab treatment achieves long-term disease-free survival in IGHV-mutated chronic lymphocytic leukemia.
- Author
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Thompson PA, Tam CS, O'Brien SM, Wierda WG, Stingo F, Plunkett W, Smith SC, Kantarjian HM, Freireich EJ, and Keating MJ
- Subjects
- Adolescent, Adult, Aged, Aged, 80 and over, Cause of Death, Cyclophosphamide administration & dosage, Female, Humans, Incidence, Leukemia, Lymphocytic, Chronic, B-Cell diagnosis, Leukemia, Lymphocytic, Chronic, B-Cell mortality, Male, Middle Aged, Neoplasm Staging, Neoplasm, Residual, Neoplasms, Second Primary epidemiology, Neoplasms, Second Primary etiology, Neoplasms, Second Primary mortality, Prognosis, Recurrence, Remission Induction, Retreatment, Rituximab administration & dosage, Survival Analysis, Treatment Outcome, Vidarabine administration & dosage, Vidarabine analogs & derivatives, Young Adult, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Immunoglobulin Heavy Chains genetics, Leukemia, Lymphocytic, Chronic, B-Cell drug therapy, Leukemia, Lymphocytic, Chronic, B-Cell genetics, Mutation
- Abstract
Accurate identification of patients likely to achieve long-progression-free survival (PFS) after chemoimmunotherapy is essential given the availability of less toxic alternatives, such as ibrutinib. Fludarabine, cyclophosphamide, and rituximab (FCR) achieved a high response rate, but continued relapses were seen in initial reports. We reviewed the original 300 patient phase 2 FCR study to identify long-term disease-free survivors. Minimal residual disease (MRD) was assessed posttreatment by a polymerase chain reaction-based ligase chain reaction assay (sensitivity 0.01%). At the median follow-up of 12.8 years, PFS was 30.9% (median PFS, 6.4 years). The 12.8-year PFS was 53.9% for patients with mutated immunoglobulin heavy chain variable (IGHV) gene (IGHV-M) and 8.7% for patients with unmutated IGHV (IGHV-UM). 50.7% of patients with IGHV-M achieved MRD-negativity posttreatment; of these, PFS was 79.8% at 12.8 years. A plateau was seen on the PFS curve in patients with IGHV-M, with no relapses beyond 10.4 years in 42 patients (total follow-up 105.4 patient-years). On multivariable analysis, IGHV-UM (hazard ratio, 3.37 [2.18-5.21]; P < .001) and del(17p) by conventional karyotyping (hazard ratio, 7.96 [1.02-61.92]; P = .048) were significantly associated with inferior PFS. Fifteen patients with IGHV-M had 4-color MRD flow cytometry (sensitivity 0.01%) performed in peripheral blood, at a median of 12.8 years posttreatment (range, 9.5-14.7). All were MRD-negative. The high rate of very long-term PFS in patients with IGHV-M after FCR argues for the continued use of chemoimmunotherapy in this patient subgroup outside clinical trials; alternative strategies may be preferred in patients with IGHV-UM, to limit long-term toxicity., (© 2016 by The American Society of Hematology.)
- Published
- 2016
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11. Second cancers and Richter transformation are the leading causes of death in patients with trisomy 12 chronic lymphocytic leukemia.
- Author
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Strati P, Abruzzo LV, Wierda WG, O'Brien S, Ferrajoli A, and Keating MJ
- Subjects
- ADP-ribosyl Cyclase 1 metabolism, Aged, Aged, 80 and over, Cause of Death, Female, Humans, In Situ Hybridization, Fluorescence, Leukemia, Lymphocytic, Chronic, B-Cell genetics, Lymphoma, Large B-Cell, Diffuse genetics, Male, Membrane Glycoproteins metabolism, Neoplasms, Second Primary genetics, Retrospective Studies, Thrombocytopenia physiopathology, Trisomy genetics, Chromosomes, Human, Pair 12, Leukemia, Lymphocytic, Chronic, B-Cell mortality, Lymphoma, Large B-Cell, Diffuse mortality, Neoplasms, Second Primary mortality, Trisomy pathology
- Abstract
Background: Trisomy 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 Methods: In order to better define this large group, we reviewed the characteristics of 250 untreated patients with +12., Results: When 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)., Conclusion: Patients with +12 CLL show characteristic clinical and biologic features, and may benefit from increased surveillance for second cancers., (Copyright © 2015 Elsevier Inc. All rights reserved.)
- Published
- 2015
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12. Three newly approved drugs for chronic lymphocytic leukemia: incorporating ibrutinib, idelalisib, and obinutuzumab into clinical practice.
- Author
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Sanford DS, Wierda WG, Burger JA, Keating MJ, and O'Brien SM
- Subjects
- Adenine analogs & derivatives, Humans, Piperidines, Antibodies, Monoclonal, Humanized therapeutic use, Antineoplastic Agents therapeutic use, Leukemia, Lymphocytic, Chronic, B-Cell drug therapy, Purines therapeutic use, Pyrazoles therapeutic use, Pyrimidines therapeutic use, Quinazolinones therapeutic use
- 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., (Copyright © 2015 Elsevier Inc. All rights reserved.)
- Published
- 2015
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13. Expression of executioner procaspases and their activation by a procaspase-activating compound in chronic lymphocytic leukemia cells.
- Author
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Patel V, Balakrishnan K, Keating MJ, Wierda WG, and Gandhi V
- Subjects
- Animals, B-Lymphocytes drug effects, B-Lymphocytes physiology, Cell Death drug effects, Cells, Cultured, Embryo, Mammalian, Enzyme Activation drug effects, Gene Expression Regulation, Enzymologic, Humans, Jurkat Cells, Leukemia, Lymphocytic, Chronic, B-Cell pathology, Leukocytes, Mononuclear drug effects, Leukocytes, Mononuclear physiology, Mice, Protein Precursors genetics, Protein Precursors metabolism, Zinc pharmacology, Caspases, Effector genetics, Caspases, Effector metabolism, Hydrazones pharmacology, Leukemia, Lymphocytic, Chronic, B-Cell enzymology, Piperazines pharmacology
- Abstract
Intrinsic and extrinsic apoptotic pathways converge to activate common downstream executioner caspases (caspase-3, -6, and -7), resulting in cell death. In chronic lymphocytic leukemia (CLL), neoplastic B cells evade apoptosis owing to the overexpression of survival proteins. We hypothesized that direct activation of procaspases could bypass the apoptosis resistance induced by the upstream prosurvival proteins. The procaspase-activating compounds (PAC-1), including B-PAC-1 (L14R8), convert inactive executioner procaspases to their active cleaved forms by chelation of labile zinc ions. Both at transcript and protein levels, primary CLL cells express high levels of latent procaspases (3, -7, and -9). B-PAC-1 treatment induced CLL lymphocyte death which was higher than that in normal peripheral blood mononuclear cells or B cells, and was independent of prognostic markers and microenvironmental factors. Mechanistically, B-PAC-1 treatment activated executioner procaspases and not other Zn-dependent enzymes. Exogenous zinc completely, and pancaspase inhibitors partially, reversed B-PAC-1-induced apoptosis, elucidating the zinc-mediated mechanism of action. The cell demise relied on the presence of caspase-3/7 but not caspase-8 or Bax/Bak proteins. B-PAC-1 in combination with an inhibitor of apoptosis protein antagonist (Smac066) synergistically induced apoptosis in CLL samples. Our investigations demonstrated that direct activation of executioner procaspases via B-PAC-1 treatment bypasses apoptosis resistance and is a novel approach for CLL therapeutics., (© 2015 by The American Society of Hematology.)
- Published
- 2015
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14. Proteasome inhibitor carfilzomib complements ibrutinib's action in chronic lymphocytic leukemia.
- Author
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Lamothe B, Cervantes-Gomez F, Sivina M, Wierda WG, Keating MJ, and Gandhi V
- Subjects
- Adenine analogs & derivatives, Aged, Apoptosis drug effects, Blotting, Western, Female, Humans, In Vitro Techniques, Male, Middle Aged, Oligopeptides administration & dosage, Piperidines, Proteasome Inhibitors administration & dosage, Pyrazoles administration & dosage, Pyrimidines administration & dosage, Tumor Cells, Cultured, Antineoplastic Combined Chemotherapy Protocols administration & dosage, Leukemia, Lymphocytic, Chronic, B-Cell
- Published
- 2015
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15. Ibrutinib increases the risk of atrial fibrillation, potentially through inhibition of cardiac PI3K-Akt signaling.
- Author
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McMullen JR, Boey EJ, Ooi JY, Seymour JF, Keating MJ, and Tam CS
- Subjects
- Adenine analogs & derivatives, Agammaglobulinaemia Tyrosine Kinase, Animals, Animals, Newborn, Atrial Fibrillation chemically induced, Gene Expression Regulation, Enzymologic drug effects, Humans, Infant, Newborn, Leukemia, Lymphocytic, Chronic, B-Cell drug therapy, Lymphoma, Mantle-Cell drug therapy, Myocytes, Cardiac drug effects, Myocytes, Cardiac metabolism, Piperidines, Protein-Tyrosine Kinases antagonists & inhibitors, Protein-Tyrosine Kinases genetics, Protein-Tyrosine Kinases metabolism, Pyrazoles therapeutic use, Pyrimidines therapeutic use, Rats, Risk Factors, Atrial Fibrillation metabolism, Phosphatidylinositol 3-Kinases metabolism, Proto-Oncogene Proteins c-akt metabolism, Pyrazoles adverse effects, Pyrimidines adverse effects, Signal Transduction drug effects
- Published
- 2014
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16. Long-term results of first salvage treatment in CLL patients treated initially with FCR (fludarabine, cyclophosphamide, rituximab).
- Author
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Tam CS, O'Brien S, Plunkett W, Wierda W, Ferrajoli A, Wang X, Do KA, Cortes J, Khouri I, Kantarjian H, Lerner S, and Keating MJ
- Subjects
- Aged, Disease Progression, Female, Follow-Up Studies, Humans, Leukemia, Lymphocytic, Chronic, B-Cell diagnosis, Leukemia, Lymphocytic, Chronic, B-Cell pathology, Male, Rituximab, Survival Analysis, Treatment Outcome, Vidarabine therapeutic use, Antibodies, Monoclonal, Murine-Derived therapeutic use, Cyclophosphamide therapeutic use, Leukemia, Lymphocytic, Chronic, B-Cell drug therapy, Salvage Therapy methods, Vidarabine analogs & derivatives
- Abstract
Although fludarabine, cyclophosphamide, and rituximab (FCR) together are established as a standard first-line treatment of younger patients with chronic lymphocytic leukemia (CLL), there is little information to guide the management of patients with CLL refractory to, or who have relapsed after, receiving frontline FCR treatment. To define optimal salvage strategy and identify patients unsuitable for retreatment with FCR, we examined the survival and treatment outcome of 300 patients enrolled in a phase 2 study of FCR. After a median 142 months of follow-up, 156 patients developed progressive CLL, with a median survival of 51 months after disease progression. The duration of first remission (REM1) was a key determinant of survival after disease progression and first salvage. Patients with a short REM1 (<3 years) had a short survival period, irrespective of salvage therapy received; these patients have high unmet medical needs and are good candidates for investigation of novel therapies. In patients with a long REM1 (≥3 years), salvage treatment with either repeat FCR or lenalidomide-based therapy results in subsequent median survival exceeding 5 years; for these patients, FCR rechallenge represents a reasonable standard of care., (© 2014 by The American Society of Hematology.)
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- 2014
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17. A phase I study of fludarabine, cytarabine, and oxaliplatin therapy in patients with relapsed or refractory acute myeloid leukemia.
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Tsimberidou AM, Keating MJ, Jabbour EJ, Ravandi-Kashani F, O'Brien S, Estey E, Bekele N, Plunkett WK Jr, Kantarjian H, and Borthakur G
- Subjects
- Adolescent, Adult, Aged, Antineoplastic Combined Chemotherapy Protocols administration & dosage, Antineoplastic Combined Chemotherapy Protocols adverse effects, Child, Cytarabine administration & dosage, Cytarabine adverse effects, Dose-Response Relationship, Drug, Drug Administration Schedule, Female, Gastrointestinal Diseases chemically induced, Humans, Hyperbilirubinemia chemically induced, Male, Middle Aged, Organoplatinum Compounds administration & dosage, Organoplatinum Compounds adverse effects, Oxaliplatin, Remission Induction, Treatment Outcome, Vidarabine administration & dosage, Vidarabine adverse effects, Vidarabine analogs & derivatives, Young Adult, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Leukemia, Myeloid, Acute drug therapy, Salvage Therapy adverse effects
- Abstract
Purpose: The 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 Methods: Between 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., Results: Of 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., Conclusion: Oxaliplatin, 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., (Copyright © 2014 Elsevier Inc. All rights reserved.)
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- 2014
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18. The proceedings of the initial meeting of the Society of Hematologic Oncology 2013.
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Freireich EJ, Kantarjian H, and Keating MJ
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- Hematology, Medical Oncology
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- 2014
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19. Blood collection methods affect cellular protein integrity: implications for clinical trial biomarkers and ZAP-70 in CLL.
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Chen LS, Keating MJ, and Gandhi V
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- Biomarkers, Tumor metabolism, Blood Specimen Collection instrumentation, Clinical Trials as Topic, Humans, Immunoblotting, Leukemia, Lymphocytic, Chronic, B-Cell metabolism, Reproducibility of Results, ZAP-70 Protein-Tyrosine Kinase metabolism, Biomarkers, Tumor blood, Blood Specimen Collection methods, Leukemia, Lymphocytic, Chronic, B-Cell blood, ZAP-70 Protein-Tyrosine Kinase blood
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- 2014
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20. Kinetics of CLL cells in tissues and blood during therapy with the BTK inhibitor ibrutinib.
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Wodarz D, Garg N, Komarova NL, Benjamini O, Keating MJ, Wierda WG, Kantarjian H, James D, O'Brien S, and Burger JA
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- Adenine analogs & derivatives, Agammaglobulinaemia Tyrosine Kinase, Aged, Aged, 80 and over, Female, Humans, Male, Middle Aged, Neoplastic Cells, Circulating metabolism, Neoplastic Cells, Circulating pathology, Piperidines, Leukemia, Lymphocytic, Chronic, B-Cell blood, Leukemia, Lymphocytic, Chronic, B-Cell drug therapy, Leukemia, Lymphocytic, Chronic, B-Cell enzymology, Leukemia, Lymphocytic, Chronic, B-Cell pathology, Models, Biological, Protein Kinase Inhibitors administration & dosage, Protein-Tyrosine Kinases antagonists & inhibitors, Pyrazoles administration & dosage, Pyrimidines administration & dosage
- Abstract
The Bruton tyrosine kinase (BTK) inhibitor ibrutinib has excellent clinical activity in patients with chronic lymphocytic leukemia (CLL). Characteristically, ibrutinib causes CLL cell redistribution from tissue sites into the peripheral blood during the initial weeks of therapy. To better characterize the dynamics of this redistribution phenomenon, we correlated serial lymphocyte counts with volumetric changes in lymph node and spleen sizes during ibrutinib therapy. Kinetic parameters were estimated by applying a mathematical model to the data. We found that during ibrutinib therapy, 1.7% ± 1.1% of blood CLL cells and 2.7% ± 0.99% of tissue CLL cells die per day. The fraction of the tissue CLL cells that was redistributed into the blood during therapy was estimated to be 23.3% ± 17% of the total tissue disease burden. These data indicate that the reduction of tissue disease burden by ibrutinib is due more to CLL cell death and less to egress from nodal compartments., (© 2014 by The American Society of Hematology.)
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- 2014
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21. Eradication of bone marrow minimal residual disease may prompt early treatment discontinuation in CLL.
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Strati P, Keating MJ, O'Brien SM, Burger J, Ferrajoli A, Jain N, Tambaro FP, Estrov Z, Jorgensen J, Challagundla P, Faderl SH, and Wierda WG
- Subjects
- Adult, Aged, Aged, 80 and over, Antibodies, Monoclonal, Murine-Derived administration & dosage, Bone Marrow drug effects, Cyclophosphamide administration & dosage, Disease-Free Survival, Female, Humans, Leukemia, Lymphocytic, Chronic, B-Cell epidemiology, Male, Middle Aged, Neoplasm, Residual, Remission Induction, Rituximab, Time Factors, Vidarabine administration & dosage, Vidarabine analogs & derivatives, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Bone Marrow pathology, Leukemia, Lymphocytic, Chronic, B-Cell drug therapy, Leukemia, Lymphocytic, Chronic, B-Cell pathology, Withholding Treatment statistics & numerical data
- Abstract
The high complete remission rate with first-line combined fludarabine, cyclophosphamide, and rituximab (FCR) begs the question of the value of minimal residual disease (MRD)-negative status as a treatment end point. We report on 237 patients with chronic lymphocytic leukemia who received first-line FCR. MRD was prospectively assessed by 4-color flow cytometry in bone marrow after course 3 and at final response assessment. After course 3 and at final response assessment, 17% and 43% of patients were MRD negative in bone marrow, respectively. A mutated immunoglobulin heavy chain variable gene and trisomy 12 were independently associated with MRD-negative status both after 3 courses of FCR and at final response assessment in multivariable analyses (MVAs). MRD-negative status was independently associated with significantly longer progression-free survival (PFS) and overall survival (OS) in MVA (P = .03 and .02, respectively). This association was confirmed also on landmark MVA at the time of MRD assessment (P = .04 and .05, respectively). MRD-negative patients had comparable PFS and OS, independent of the number of courses received or interim staging. Early MRD eradication may be a desirable goal, prompting consideration of early discontinuation of treatment. This trial was registered at www.clinicaltrials.gov as #NCT00759798., (© 2014 by The American Society of Hematology.)
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- 2014
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22. Stimulation of the B-cell receptor activates the JAK2/STAT3 signaling pathway in chronic lymphocytic leukemia cells.
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Rozovski U, Wu JY, Harris DM, Liu Z, Li P, Hazan-Halevy I, Ferrajoli A, Burger JA, O'Brien S, Jain N, Verstovsek S, Wierda WG, Keating MJ, and Estrov Z
- Subjects
- Antibodies, Anti-Idiotypic pharmacology, Humans, Leukemia, Lymphocytic, Chronic, B-Cell pathology, Phosphorylation drug effects, Signal Transduction drug effects, Tumor Cells, Cultured, Tyrosine metabolism, Janus Kinase 2 metabolism, Leukemia, Lymphocytic, Chronic, B-Cell metabolism, Lymphocyte Activation physiology, Receptors, Antigen, B-Cell metabolism, STAT3 Transcription Factor metabolism
- Abstract
In chronic lymphocytic leukemia (CLL), stimulation of the B-cell receptor (BCR) triggers survival signals. Because in various cells activation of the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway provides cells with survival advantage, we wondered whether BCR stimulation activates the JAK/STAT pathway in CLL cells. To stimulate the BCR we incubated CLL cells with anti-IgM antibodies. Anti-IgM antibodies induced transient tyrosine phosphorylation and nuclear localization of phosphorylated (p) STAT3. Immunoprecipitation studies revealed that anti-JAK2 antibodies coimmunoprecipitated pSTAT3 and pJAK2 in IgM-stimulated but not unstimulated CLL cells, suggesting that activation of the BCR induces activation of JAK2, which phosphorylates STAT3. Incubation of CLL cells with the JAK1/2 inhibitor ruxolitinib inhibited IgM-induced STAT3 phosphorylation and induced apoptosis of IgM-stimulated but not unstimulated CLL cells in a dose- and time-dependent manner. Whether ruxolitinib treatment would benefit patients with CLL remains to be determined., (© 2014 by The American Society of Hematology.)
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- 2014
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23. Evaluation of bendamustine in combination with fludarabine in primary chronic lymphocytic leukemia cells.
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El-Mabhouh AA, Ayres ML, Shpall EJ, Baladandayuthapani V, Keating MJ, Wierda WG, and Gandhi V
- Subjects
- Apoptosis drug effects, Bendamustine Hydrochloride, Bone Marrow Cells drug effects, Bone Marrow Cells physiology, Cells, Cultured, Drug Administration Schedule, Drug Evaluation, Preclinical, Humans, Leukemia, Lymphocytic, Chronic, B-Cell pathology, Primary Cell Culture, Stromal Cells drug effects, Stromal Cells physiology, Time Factors, Vidarabine administration & dosage, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Leukemia, Lymphocytic, Chronic, B-Cell drug therapy, Nitrogen Mustard Compounds administration & dosage, Vidarabine analogs & derivatives
- Abstract
The fludarabine and cyclophosphamide couplet has become the backbone of the chronic lymphocytic leukemia (CLL) standard of care. Although this is an effective treatment, it results in untoward toxicity. Bendamustine is a newly approved and better-tolerated alkylating agent. We hypothesized that similar to cyclophosphamide, bendamustine-induced DNA damage will be inhibited by fludarabine, resulting in increased cytotoxicity. To test this hypothesis and the role of the stromal microenvironment in this process, we treated CLL lymphocytes in vitro with each drug alone and in combination. Simultaneous or prior addition of fludarabine to bendamustine resulted in maximum cytotoxicity assayed by 3,3'-dihexyloxacarbocyanine iodine negativity, annexin positivity, and poly (adenosine 5'-diphosphate-ribose) polymerase cleavage. Cytotoxicity elicited by combination of both agents was similar in these malignant B cells cultured either in suspension or on marrow stroma cells. Cell death was associated with DNA damage response, which was determined by phosphorylation of H2AX and unscheduled DNA synthesis. H2AX activation was maximum with the drug combination, and unscheduled DNA synthesis induced by bendamustine was blocked by fludarabine. In parallel, ATM, Chk2, and p53 were phosphorylated and PUMA was induced. Cell death was caspase independent; however, caspases did decrease levels of Mcl-1 survival protein. These data provide a rationale for combining fludarabine with bendamustine for patients with CLL., (© 2014 by The American Society of Hematology.)
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- 2014
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24. Correlation between FDG/PET, histology, characteristics, and survival in 332 patients with chronic lymphoid leukemia.
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Falchi L, Keating MJ, Marom EM, Truong MT, Schlette EJ, Sargent RL, Trinh L, Wang X, Smith SC, Jain N, Estrov Z, O'Brien S, Wierda WG, Lerner S, and Ferrajoli A
- Subjects
- Adult, Aged, Aged, 80 and over, Biopsy methods, Female, Humans, Leukemia, Lymphocytic, Chronic, B-Cell therapy, Male, Middle Aged, Treatment Outcome, Fluorodeoxyglucose F18, Leukemia, Lymphocytic, Chronic, B-Cell diagnosis, Leukemia, Lymphocytic, Chronic, B-Cell mortality, Positron-Emission Tomography
- Abstract
Richter syndrome (RS) is associated with poor outcome. The prognosis of patients with histologically aggressive chronic lymphocytic leukemia (CLL), or HAC, has not been studied. We aimed to correlate 2-deoxy-2-[(18)F]fluoroglucose/positron emission tomography (FDG/PET) data, histological diagnosis, clinical characteristics, and survival in patients with CLL. A total of 332 patients with CLL were histologically classified as: 95 RS, 117 HAC, and 120 histologically indolent CLL (HIC). HAC and RS patients had higher maximum standardized uptake value (SUVmax), more frequent constitutional symptoms, poorer performance status (PS), lower hemoglobin and platelets, and higher lactate dehydrogenase and β-2-microglobulin. An SUVmax ≥10 strongly correlated with mortality (overall survival [OS], 56.7 vs 6.9 months in patients with SUVmax <10 vs ≥10). Survival of patients with RS and HAC was similar among patients with SUVmax <10 or ≥10. SUVmax ≥10, PS ≥2, bulky disease, and age ≥65 were independently associated with shorter OS. In patients undergoing both fine-needle aspiration and biopsy, the former proved diagnostically inadequate in 23%, 29%, and 53% of HIC, HAC, and RS, respectively. FDG/PET is a useful diagnostic tool in patients with CLL and suspected transformation. Patients with HAC show different characteristics and worse prognosis compared with those with HIC. Patients with different CLL phases, but similar SUVmax have similar outcome. Tissue biopsy should be preferred for diagnosing RS.
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- 2014
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25. Statin and aspirin use is associated with improved outcome of FCR therapy in relapsed/refractory chronic lymphocytic leukemia.
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Chae YK, Trinh L, Jain P, Wang X, Rozovski U, Wierda WG, Keating MJ, and Estrov Z
- Subjects
- Adult, Aged, Aged, 80 and over, Antibodies, Monoclonal, Murine-Derived administration & dosage, Cyclophosphamide administration & dosage, Drug Synergism, Humans, Leukemia, Lymphocytic, Chronic, B-Cell diagnosis, Leukemia, Lymphocytic, Chronic, B-Cell mortality, Middle Aged, Retrospective Studies, Rituximab, Salvage Therapy, Treatment Outcome, Vidarabine administration & dosage, Vidarabine analogs & derivatives, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Aspirin therapeutic use, Hydroxymethylglutaryl-CoA Reductase Inhibitors therapeutic use, Leukemia, Lymphocytic, Chronic, B-Cell drug therapy
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- 2014
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26. The Spiegelmer NOX-A12, a novel CXCL12 inhibitor, interferes with chronic lymphocytic leukemia cell motility and causes chemosensitization.
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Hoellenriegel J, Zboralski D, Maasch C, Rosin NY, Wierda WG, Keating MJ, Kruschinski A, and Burger JA
- Subjects
- Cells, Cultured, Chemokine CXCL12 pharmacology, Drug Evaluation, Preclinical, Drug Synergism, Humans, Jurkat Cells, Lymphocytes drug effects, Lymphocytes physiology, Mesenchymal Stem Cells drug effects, Mesenchymal Stem Cells physiology, Recombinant Proteins pharmacology, Transcellular Cell Migration drug effects, Antineoplastic Agents pharmacology, Aptamers, Nucleotide pharmacology, Cell Movement drug effects, Chemokine CXCL12 antagonists & inhibitors, Drug Resistance, Neoplasm drug effects, Leukemia, Lymphocytic, Chronic, B-Cell pathology
- Abstract
The CXC chemokine ligand (CXCL12, or stromal cell-derived factor-1 as previously known) plays a critical role for homing and retention of chronic lymphocytic leukemia (CLL) cells in tissues such as the bone marrow (BM). In tissues, stromal cells constitutively secrete and present CXCL12 via cell-surface-bound glycosaminoglycans (GAGs), thereby attracting CLL cells and protecting them from cytotoxic drugs, a mechanism that may account for residual disease after conventional CLL therapy. NOX-A12, an RNA oligonucleotide in L-configuration (Spiegelmer) that binds and neutralizes CXCL12, was developed for interference with CXCL12 in the tumor microenvironment and for cell mobilization. Here, we examined effects of NOX-A12 on CLL cell migration and drug sensitivity. We found that NOX-A12 effectively inhibited CXCL12-induced chemotaxis of CLL cells. In contrast, NOX-A12 increased CLL migration underneath a confluent layer of BM stromal cells (BMSCs) due to interference with the CXCL12 gradient established by BMSCs. In particular, NOX-A12 competes with GAGs such as heparin for CXCL12 binding, leading to the release of CXCL12 from stromal cell-surface-bound GAGs, and thereby to neutralization of the chemokine. Furthermore, NOX-A12 sensitizes CLL cells toward bendamustine and fludarabine in BMSC cocultures. These data demonstrate that NOX-A12 effectively interferes with CLL cell migration and BMSC-mediated drug resistance, and establishes a rationale for clinical development of NOX-A12 in combination with conventional agents in CLL.
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- 2014
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27. Phase I-II clinical trial of oxaliplatin, fludarabine, cytarabine, and rituximab therapy in aggressive relapsed/refractory chronic lymphocytic leukemia or Richter syndrome.
- Author
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Tsimberidou AM, Wierda WG, Wen S, Plunkett W, O'Brien S, Kipps TJ, Jones JA, Badoux X, Kantarjian H, and Keating MJ
- Subjects
- Antibodies, Monoclonal, Murine-Derived administration & dosage, Antineoplastic Combined Chemotherapy Protocols adverse effects, Cytarabine administration & dosage, Disease Progression, Hematopoietic Stem Cell Transplantation, Humans, Leukemia, Lymphocytic, Chronic, B-Cell mortality, Leukemia, Lymphocytic, Chronic, B-Cell pathology, Neoplasm Staging, Organoplatinum Compounds administration & dosage, Oxaliplatin, Recurrence, Rituximab, Transplantation, Homologous, Treatment Outcome, Vidarabine administration & dosage, Vidarabine analogs & derivatives, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Leukemia, Lymphocytic, Chronic, B-Cell drug therapy
- Abstract
Background: To improve outcomes of patients with Richter syndrome (RS) and relapsed/refractory chronic lymphocytic leukemia (CLL), we modified the OFAR1 regimen (oxaliplatin and cytarabine doses of the oxaliplatin, fludarabine, cytarabine, and rituximab) for this phase I-II study (OFAR2)., Patients and Methods: OFAR2 consisted of oxaliplatin at 30 mg/m(2) on days 1 to 4, fludarabine at 30 mg/m(2), cytarabine at 0.5 g/m(2), rituximab at 375 mg/m(2) on day 3, and pegfilgrastim at 6 mg on day 6. Fludarabine and cytarabine were given on days 2 and 3 (cohort 1), days 2 to 4 (cohort 2), or days 2 to 5 (cohort 3) every 4 weeks. Phase II followed the "3 + 3" design of phase I., Results: The 102 patients (CLL, 67; RS, 35) treated had heavily pretreated high-risk disease. Twelve patients were treated in phase I; cohort 2 was the phase II recommended dose. The most common toxicities were hematologic. Response rates (phase II) were 38.7% for RS (complete response [CR], 6.5%) and 50.8% for relapsed/refractory CLL (CR, 4.6%). The median survival durations were 6.6 (RS) and 20.6 (CLL) months. Among 9 patients who underwent allogeneic stem cell transplantation (SCT) as post-remission therapy, none has died (median follow-up, 15.9 months)., Conclusion: OFAR2 had significant antileukemic activity in RS and relapsed/refractory CLL. Patients undergoing SCT as post-remission therapy had favorable outcomes., (Copyright © 2013 Elsevier Inc. All rights reserved.)
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- 2013
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28. CD4(-)/CD8(-) variant of T-cell large granular lymphocytic leukemia or hepatosplenic T-cell lymphoma: a clinicopathologic dilemma.
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Benjamini O, Jain P, Konoplev SN, Yin CC, Abruzzo L, Wotherspoon AC, Dearden C, Shpall EJ, Estrov Z, and Keating MJ
- Subjects
- Bone Marrow pathology, CD4 Antigens metabolism, CD8 Antigens metabolism, Humans, Leukemia, Large Granular Lymphocytic diagnosis, Leukemia, Large Granular Lymphocytic metabolism, Male, Middle Aged, Receptors, Antigen, T-Cell, gamma-delta genetics, Receptors, Antigen, T-Cell, gamma-delta metabolism, Spleen pathology, Leukemia, Large Granular Lymphocytic pathology
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- 2013
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29. Prognostic value of miR-155 in individuals with monoclonal B-cell lymphocytosis and patients with B chronic lymphocytic leukemia.
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Ferrajoli A, Shanafelt TD, Ivan C, Shimizu M, Rabe KG, Nouraee N, Ikuo M, Ghosh AK, Lerner S, Rassenti LZ, Xiao L, Hu J, Reuben JM, Calin S, You MJ, Manning JT, Wierda WG, Estrov Z, O'Brien S, Kipps TJ, Keating MJ, Kay NE, and Calin GA
- Subjects
- Adult, Aged, Aged, 80 and over, B-Lymphocytes pathology, Biomarkers, Tumor blood, Biomarkers, Tumor genetics, Cohort Studies, Disease Progression, Female, Gene Expression, Humans, In Situ Hybridization, Fluorescence, Kaplan-Meier Estimate, Leukemia, Lymphocytic, Chronic, B-Cell blood, Leukemia, Lymphocytic, Chronic, B-Cell drug therapy, Lymphocytosis blood, Lymphocytosis drug therapy, Male, MicroRNAs blood, Microvessels metabolism, Middle Aged, Multivariate Analysis, Prognosis, Reverse Transcriptase Polymerase Chain Reaction, Treatment Outcome, B-Lymphocytes metabolism, Leukemia, Lymphocytic, Chronic, B-Cell genetics, Lymphocytosis genetics, MicroRNAs genetics
- Abstract
Noncoding RNAs play a pivotal role in the pathogenesis of chronic lymphocytic leukemia (CLL). We hypothesized that microRNAs (miRs) are involved in the transition from monoclonal B-cell lymphocytosis (MBL) to CLL and tested miR-15a/16-1 cluster, miR-21, and miR-155 expression in purified B cells of normal individuals, individuals with MBL, and patients with CLL. When we analyzed 224 samples from 2 independent training and validation cohorts, we found that miR-155 was overexpressed in B cells from individuals with MBL, and even more so in B cells from patients with CLL, when compared with B cells from normal individuals. Furthermore, we were able to identify miR-155 in circulating microvesicles from both individuals with MBL and patients with CLL. Next, to examine the prognostic role of miR-155, we measured its expression level in plasma samples collected before treatment initiation in 228 patients with CLL. We found significantly higher miR-155 expression levels in patients who failed to achieve a complete response compared with those who experienced complete response. Our findings support the use of cellular and plasma levels of miR-155 as biomarkers for the risk of progression in individuals with MBL, as well as to identify patients with CLL who may not respond well to therapy.
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- 2013
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30. Retrospect of hematological malignancies 2012.
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Freireich EJ, Kantarjian H, and Keating MJ
- Subjects
- Hematology, Humans, Medical Oncology, Societies, Medical, Hematologic Neoplasms pathology
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- 2013
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31. Lenalidomide induces long-lasting responses in elderly patients with chronic lymphocytic leukemia.
- Author
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Strati P, Keating MJ, Wierda WG, Badoux XC, Calin S, Reuben JM, O'Brien S, Kornblau SM, Kantarjian HM, Gao H, and Ferrajoli A
- Subjects
- Aged, Aged, 80 and over, Angiogenesis Inhibitors adverse effects, Angiogenesis Inhibitors therapeutic use, Antineoplastic Agents adverse effects, Antineoplastic Agents therapeutic use, Disease-Free Survival, Female, Humans, Lenalidomide, Leukemia, Lymphocytic, Chronic, B-Cell immunology, Leukemia, Lymphocytic, Chronic, B-Cell pathology, Lymphocyte Count, Male, Neoplasm, Residual, Remission Induction, T-Lymphocytes pathology, Thalidomide adverse effects, Thalidomide therapeutic use, Time Factors, Leukemia, Lymphocytic, Chronic, B-Cell drug therapy, Thalidomide analogs & derivatives
- Abstract
We evaluated long-term outcomes of 60 patients with chronic lymphocytic leukemia treated with an initial therapy of lenalidomide. At a median follow-up of 4 years, time-to-treatment failure has not been reached and overall survival is 82%. Thirty-five (58%) patients had a response lasting >36 months (long-term responders [LTRs]). Best LTR responses consisted of 25 (71%) complete remissions and 10 (29%) partial remissions. In addition to clinical responses, an increase in IgA, IgG, and IgM levels of >50% from baseline was reported in 61%, 45%, and 42% of LTRs. Normalization in the percentage of CD4+ and CD8+ cells and T-cell numbers was observed in 48%, 71% and 99% of LTRs. Compared with other patients in the study, LTRs had lower baseline plasma levels of β-2-microglobulin, were more likely to have trisomy 12, and less likely to have deletion 17p.
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- 2013
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32. Azacitidine in fludarabine-refractory chronic lymphocytic leukemia: a phase II study.
- Author
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Malik A, Shoukier M, Garcia-Manero G, Wierda W, Cortes J, Bickel S, Keating MJ, and Estrov Z
- Subjects
- Aged, Aged, 80 and over, Antimetabolites, Antineoplastic adverse effects, Azacitidine adverse effects, DNA Methylation drug effects, Female, Humans, Leukemia, Lymphocytic, Chronic, B-Cell drug therapy, Leukemia, Lymphocytic, Chronic, B-Cell genetics, Male, Middle Aged, Treatment Outcome, Antimetabolites, Antineoplastic therapeutic use, Azacitidine therapeutic use
- Abstract
Background: Treatment of fludarabine-refractory disease in patients with chronic lymphocytic leukemia (CLL) remains a challenge. Because a recent genome-wide methylation analysis of CLL cells suggested that demethylation therapy might be beneficial in CLL, we conducted a phase II trial with the hypomethylating agent azacitidine in patients with recurrent fludarabine-refractory CLL., Patients and Methods: Nine patients with recurrent fludarabine-refractory Rai stage IV CLL (median age, 74 years; range, 49-81 years) were enrolled. Azacitidine (75 mg/m(2)) was administered by subcutaneous injection daily for 7 consecutive days every 3 to 8 weeks, and the data were analyzed at a median follow-up of 9 months (range 3-47 months)., Results: The trial was prematurely discontinued because of lack of response and slow accrual. The number of cycles administered ranged from 1 to 6. Three patients received 1 cycle, 3 patients received 2 cycles, and the remaining 3 patients received 4, 5, or 6 cycles. Side effects included grade 2 or 3 infectious episodes (resulting from immunosuppression and drug-induced neutropenia), diarrhea, rash, vomiting, anemia, and thrombocytopenia. One patient experienced reduction of hepatosplenomegaly and a substantial increase in platelet count after 4 cycles of therapy. However this response did not qualify as a partial response according to the National Cancer Institute International Workshop on CLL (NCI-IWCLL) criteria. At a median follow-up of 9 months after the start of azacitidine treatment, 3 patients (33%) who went on to receive other treatments were alive., Conclusions: Although no partial or complete responses occurred in these heavily pretreated patients, the encouraging response in 1 of these patients may warrant further studies to investigate the effects of azacitidine in CLL., (Copyright © 2013 Elsevier Inc. All rights reserved.)
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- 2013
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33. Genomic variation by whole-genome SNP mapping arrays predicts time-to-event outcome in patients with chronic lymphocytic leukemia: a comparison of CLL and HapMap genotypes.
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Schweighofer CD, Coombes KR, Majewski T, Barron LL, Lerner S, Sargent RL, O'Brien S, Ferrajoli A, Wierda WG, Czerniak BA, Medeiros LJ, Keating MJ, and Abruzzo LV
- Subjects
- Adult, Aged, Chromosome Aberrations, DNA Copy Number Variations, Female, Follow-Up Studies, Genomics, Genotype, Humans, Male, Middle Aged, Oligonucleotide Array Sequence Analysis, Prognosis, Genome, Human, Leukemia, Lymphocytic, Chronic, B-Cell genetics, Leukemia, Lymphocytic, Chronic, B-Cell mortality, Polymorphism, Single Nucleotide
- Abstract
Genomic abnormalities, such as deletions in 11q22 or 17p13, are associated with poorer prognosis in patients with chronic lymphocytic leukemia (CLL). We hypothesized that unknown regions of copy number variation (CNV) affect clinical outcome and can be detected by array-based single-nucleotide polymorphism (SNP) genotyping. We compared SNP genotypes from 168 untreated patients with CLL with genotypes from 73 white HapMap controls. We identified 322 regions of recurrent CNV, 82 of which occurred significantly more often in CLL than in HapMap (CLL-specific CNV), including regions typically aberrant in CLL: deletions in 6q21, 11q22, 13q14, and 17p13 and trisomy 12. In univariate analyses, 35 of total and 11 of CLL-specific CNVs were associated with unfavorable time-to-event outcomes, including gains or losses in chromosomes 2p, 4p, 4q, 6p, 6q, 7q, 11p, 11q, and 17p. In multivariate analyses, six CNVs (ie, CLL-specific variations in 11p15.1-15.4 or 6q27) predicted time-to-treatment or overall survival independently of established markers of prognosis. Moreover, genotypic complexity (ie, the number of independent CNVs per patient) significantly predicted prognosis, with a median time-to-treatment of 64 months versus 23 months in patients with zero to one versus two or more CNVs, respectively (P = 3.3 × 10(-8)). In summary, a comparison of SNP genotypes from patients with CLL with HapMap controls allowed us to identify known and unknown recurrent CNVs and to determine regions and rates of CNV that predict poorer prognosis in patients with CLL., (Copyright © 2013 American Society for Investigative Pathology and the Association for Molecular Pathology. Published by Elsevier Inc. All rights reserved.)
- Published
- 2013
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34. Risk categories and refractory CLL in the era of chemoimmunotherapy.
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Zenz T, Gribben JG, Hallek M, Döhner H, Keating MJ, and Stilgenbauer S
- Subjects
- Algorithms, Antibodies, Monoclonal, Murine-Derived administration & dosage, Antimetabolites, Antineoplastic pharmacology, Chromosome Deletion, Chromosomes, Human, Pair 17 genetics, Chromosomes, Human, Pair 17 ultrastructure, Clinical Trials as Topic statistics & numerical data, Combined Modality Therapy, Drug Resistance, Neoplasm, Forecasting, Genes, p53, Humans, Immunotherapy, Leukemia, Lymphocytic, Chronic, B-Cell drug therapy, Leukemia, Lymphocytic, Chronic, B-Cell genetics, Leukemia, Lymphocytic, Chronic, B-Cell pathology, Leukemia, Lymphocytic, Chronic, B-Cell therapy, Models, Biological, Prognosis, Risk Assessment, Rituximab, Terminology as Topic, Treatment Failure, Vidarabine analogs & derivatives, Vidarabine pharmacology, Leukemia, Lymphocytic, Chronic, B-Cell classification
- Abstract
Standardized criteria for diagnosis and response evaluation in chronic lymphocytic leukemia (CLL) are essential to achieve comparability of results and improvement of clinical care. With the increasing range of therapeutic options, the treatment context is important when defining refractory CLL. Refractory CLL has been defined as no response or response lasting ≤ 6 months from last therapy. This subgroup has a very poor outcome, and many trials use this group as an entry point for early drug development. With the intensification of first-line regimens, the proportion of patients with refractory CLL using these criteria decreases. This has immediate consequences for recruitment of patients into trials as well as salvage strategies. Conversely, patients who are not refractory according to the traditional definition but who have suboptimal or short response to intense therapy also have a very poor outcome. In this Perspective, we discuss recent results that may lead to a reassessment of risk categories in CLL focusing on fit patients who are eligible for all treatment options. We cover aspects of the history and biologic basis for refractory CLL and will focus on how emerging data on treatment failure from large trials using chemoimmunotherapy may help to define risk groups in CLL.
- Published
- 2012
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35. The Bruton tyrosine kinase inhibitor PCI-32765 thwarts chronic lymphocytic leukemia cell survival and tissue homing in vitro and in vivo.
- Author
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Ponader S, Chen SS, Buggy JJ, Balakrishnan K, Gandhi V, Wierda WG, Keating MJ, O'Brien S, Chiorazzi N, and Burger JA
- Subjects
- Adenine analogs & derivatives, Agammaglobulinaemia Tyrosine Kinase, Animals, Antineoplastic Agents pharmacology, Antineoplastic Agents therapeutic use, Cell Survival drug effects, Cells, Cultured, Humans, Leukemic Infiltration pathology, Mice, Mice, Inbred C3H, Mice, Inbred C57BL, Mice, SCID, Mice, Transgenic, Piperidines, Protein Kinase Inhibitors pharmacology, Protein Kinase Inhibitors therapeutic use, Protein-Tyrosine Kinases antagonists & inhibitors, Pyrazoles therapeutic use, Pyrimidines therapeutic use, Xenograft Model Antitumor Assays, Chemotaxis, Leukocyte drug effects, Leukemia, Lymphocytic, Chronic, B-Cell drug therapy, Leukemia, Lymphocytic, Chronic, B-Cell pathology, Leukemic Infiltration prevention & control, Pyrazoles pharmacology, Pyrimidines pharmacology
- Abstract
B-cell receptor (BCR) signaling is a critical pathway in the pathogenesis of several B-cell malignancies, including chronic lymphocytic leukemia (CLL), and can be targeted by inhibitors of BCR-associated kinases, such as Bruton tyrosine kinase (Btk). PCI-32765, a selective, irreversible Btk inhibitor, is a novel, molecularly targeted agent for patients with B-cell malignancies, and is particularly active in patients with CLL. In this study, we analyzed the mechanism of action of PCI-32765 in CLL, using in vitro and in vivo models, and performed correlative studies on specimens from patients receiving therapy with PCI-32765. PCI-32765 significantly inhibited CLL cell survival, DNA synthesis, and migration in response to tissue homing chemokines (CXCL12, CXCL13). PCI-32765 also down-regulated secretion of BCR-dependent chemokines (CCL3, CCL4) by the CLL cells, both in vitro and in vivo. In an adoptive transfer TCL1 mouse model of CLL, PCI-32765 affected disease progression. In this model, PCI-32765 caused a transient early lymphocytosis, and profoundly inhibited CLL progression, as assessed by weight, development, and extent of hepatospenomegaly, and survival. Our data demonstrate that PCI-32765 effectively inhibits CLL cell migration and survival, possibly explaining some of the characteristic clinical activity of this new targeted agent.
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- 2012
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36. Histone deacetylases mediate the silencing of miR-15a, miR-16, and miR-29b in chronic lymphocytic leukemia.
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Sampath D, Liu C, Vasan K, Sulda M, Puduvalli VK, Wierda WG, and Keating MJ
- Subjects
- Adult, Benzamides pharmacology, Female, Gene Expression Regulation, Leukemic drug effects, Histone Deacetylase Inhibitors pharmacology, Histone Deacetylases genetics, Humans, Hydroxamic Acids pharmacology, Indoles, Leukemia, Lymphocytic, Chronic, B-Cell pathology, Male, Panobinostat, Primary Cell Culture, Pyridines pharmacology, Tumor Cells, Cultured, Gene Silencing drug effects, Gene Silencing physiology, Histone Deacetylases physiology, Leukemia, Lymphocytic, Chronic, B-Cell genetics, MicroRNAs genetics
- Abstract
Chronic lymphocytic leukemia (CLL) demonstrates a global down-regulation of miR-15a and miR-16 and a selective silencing of the related miR-29b in aggressive disease. Deletions in chromosome 13 [del(13q14)] partially account for the loss of expression of miR-15a and miR-16, but the mechanisms by which miR-29b becomes silenced is unknown. In the present study, we show that the histone deacetylases (HDACs) are overexpressed in CLL and mediate the epigenetic silencing of miR-15a, miR-16, and miR-29b. HDAC inhibition triggered the accumulation of the transcriptionally activating chromatin modification H3K4me2 and restored the expression of miR-15a, miR-16, and miR-29b in approximately 35% of samples. Ectopic expression of miR-15a and miR-16 and HDAC inhibition-induced expression of miR-15a, miR-16, or miR-29b in primary CLL cells was associated with declines in the levels of Mcl-1, but not Bcl-2, mitochondrial dysfunction, and induction of cell death. Therefore, our results show that HDACs aberrantly silence the expression of the critical tumor suppressors miR-15a, miR-16, and miR-29b in CLL. Deacetylase inhibition may be a therapeutic strategy that restores the expression of these miRs to antagonize Mcl-1, an important survival protein in these cells. Consequently, CLL patients who exhibit such epigenetic silencing may benefit from HDAC inhibitor-based therapy.
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- 2012
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37. The phosphoinositide 3'-kinase delta inhibitor, CAL-101, inhibits B-cell receptor signaling and chemokine networks in chronic lymphocytic leukemia.
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Hoellenriegel J, Meadows SA, Sivina M, Wierda WG, Kantarjian H, Keating MJ, Giese N, O'Brien S, Yu A, Miller LL, Lannutti BJ, and Burger JA
- Subjects
- Antineoplastic Agents therapeutic use, Cell Movement drug effects, Cell Survival drug effects, Cells, Cultured, Chemokines metabolism, Class I Phosphatidylinositol 3-Kinases, Down-Regulation drug effects, Drug Evaluation, Preclinical, Humans, Leukemia, Lymphocytic, Chronic, B-Cell drug therapy, Leukemia, Lymphocytic, Chronic, B-Cell metabolism, Metabolic Networks and Pathways drug effects, Metabolic Networks and Pathways physiology, Phosphoinositide-3 Kinase Inhibitors, Purines therapeutic use, Quinazolinones therapeutic use, Signal Transduction drug effects, Chemokines antagonists & inhibitors, Leukemia, Lymphocytic, Chronic, B-Cell pathology, Purines pharmacology, Quinazolinones pharmacology, Receptors, Antigen, B-Cell antagonists & inhibitors
- Abstract
In lymphocytes, the phosphoinositide 3'-kinase (PI3K) isoform p110δ (PI3Kδ) transmits signals from surface receptors, including the B-cell receptor (BCR). CAL-101, a selective inhibitor of PI3Kδ, displays clinical activity in CLL, causing rapid lymph node shrinkage and a transient lymphocytosis. Inhibition of pro-survival pathways, the presumed mechanism of CAL-101, does not explain this characteristic pattern of activity. Therefore, we tested CAL-101 in assays that model CLL-microenvironment interactions in vitro. We found that CAL-101 inhibits CLL cell chemotaxis toward CXCL12 and CXCL13 and migration beneath stromal cells (pseudoemperipolesis). CAL-101 also down-regulates secretion of chemokines in stromal cocultures and after BCR triggering. CAL-101 reduces survival signals derived from the BCR or from nurse-like cells, and inhibits BCR- and chemokine-receptor-induced AKT and MAP kinase (ERK) activation. In stromal cocultures, CAL-101 sensitizes CLL cells toward bendamustine, fludarabine, and dexamethasone. These results are corroborated by clinical data showing marked reductions in circulating CCL3, CCL4, and CXCL13 levels, and a surge in lymphocytosis during CAL-101 treatment. Thus, CAL-101 displays a dual mechanism of action, directly decreasing cell survival while reducing interactions that retain CLL cells in protective tissue microenvironments. These data provide an explanation for the clinical activity of CAL-101, and a roadmap for future therapeutic development.
- Published
- 2011
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38. Lenalidomide as initial therapy of elderly patients with chronic lymphocytic leukemia.
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Badoux XC, Keating MJ, Wen S, Lee BN, Sivina M, Reuben J, Wierda WG, O'Brien SM, Faderl S, Kornblau SM, Burger JA, and Ferrajoli A
- Subjects
- Administration, Oral, Aged, 80 and over, Antineoplastic Agents administration & dosage, Antineoplastic Agents therapeutic use, Dose-Response Relationship, Drug, Drug Administration Schedule, Female, Follow-Up Studies, Humans, Lenalidomide, Leukemia, Lymphocytic, Chronic, B-Cell blood, Leukemia, Lymphocytic, Chronic, B-Cell immunology, Leukemia, Lymphocytic, Chronic, B-Cell mortality, Lymphocyte Subsets cytology, Lymphocyte Subsets drug effects, Male, Neoadjuvant Therapy, Thalidomide administration & dosage, Thalidomide therapeutic use, Aged, Leukemia, Lymphocytic, Chronic, B-Cell drug therapy, Thalidomide analogs & derivatives
- Abstract
The best initial therapy for elderly patients with chronic lymphocytic leukemia (CLL) has not yet been defined. We investigated the activity of lenalidomide as initial therapy for elderly patients with CLL. Sixty patients with CLL 65 years of age and older received treatment with lenalidomide orally 5 mg daily for 56 days, then titrated up to 25 mg/d as tolerated. Treatment was continued until disease progression. At a median follow-up of 29 months, 53 patients (88%) are alive and 32 patients (53%) remain on therapy. Estimated 2-year progression-free survival is 60%. The overall response rate to lenalidomide therapy is 65%, including 10% complete response, 5% complete response with residual cytopenia, 7% nodular partial response, and 43% partial response. Neutropenia is the most common grade 3 or 4 treatment-related toxicity observed in 34% of treatment cycles. Major infections or neutropenic fever occurred in 13% of patients. Compared with baseline levels, we noted an increase in serum immunoglobulin levels across all classes, and a reduction in CCL3 and CCL4 plasma levels was noted in responding patients. Lenalidomide therapy was well tolerated and induced durable remissions in this population of elderly, symptomatic patients with CLL. This study was registered at www.clinicaltrials.gov as #NCT00535873.
- Published
- 2011
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39. Frontline chemoimmunotherapy with fludarabine, cyclophosphamide, alemtuzumab, and rituximab for high-risk chronic lymphocytic leukemia.
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Parikh SA, Keating MJ, O'Brien S, Wang X, Ferrajoli A, Faderl S, Burger J, Koller C, Estrov Z, Badoux X, Lerner S, and Wierda WG
- Subjects
- Adult, Aged, Alemtuzumab, Antibodies, Monoclonal adverse effects, Antibodies, Monoclonal, Humanized, Antibodies, Monoclonal, Murine-Derived administration & dosage, Antibodies, Monoclonal, Murine-Derived adverse effects, Antibodies, Neoplasm administration & dosage, Antibodies, Neoplasm adverse effects, Chromosome Deletion, Chromosomes, Human, Pair 17, Combined Modality Therapy, Cyclophosphamide administration & dosage, Disease-Free Survival, Female, Humans, Kaplan-Meier Estimate, Leukemia, Lymphocytic, Chronic, B-Cell genetics, Male, Middle Aged, Neutropenia etiology, Remission Induction, Risk Factors, Rituximab, Smith-Magenis Syndrome, Thrombocytopenia etiology, Vidarabine administration & dosage, Vidarabine adverse effects, Vidarabine analogs & derivatives, Antibodies, Monoclonal administration & dosage, Antineoplastic Combined Chemotherapy Protocols adverse effects, Leukemia, Lymphocytic, Chronic, B-Cell drug therapy, Leukemia, Lymphocytic, Chronic, B-Cell therapy
- Abstract
Frontline chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab (FCR) is associated with superior overall survival (OS) for patients with chronic lymphocytic leukemia (CLL). Alemtuzumab (A) was added to FCR (CFAR) in a phase 2 trial for high-risk untreated patients < 70 years with serum β-2 microglobulin (β2M) ≥ 4 mg/L. Sixty patients were enrolled; median age was 59 years (range, 42-69); 75% were male; median β2M was 5.1 mg/L (range, 4-11.6); and 51% were Rai III-IV. Complete remission (CR) was achieved in 70%, partial remission (PR) in 18%, nodular PR in 3%, for an overall response of 92%. Of 14 patients with 17p deletion, CR was achieved by 8 (57%). Of 57 BM samples evaluated by 3-color flow cytometry at the end of treatment, 41 (72%) were negative for residual disease. Grade 3-4 neutropenia and thrombocytopenia occurred with 33% and 13% courses, respectively. The median progression-free survival was 38 months and median OS was not reached. In conclusion, CFAR is an active frontline regimen for high-risk CLL. Response rates and survival are comparable with historic high-risk FCR-treated patients. CFAR may be a useful frontline regimen to achieve CR in patients with 17p deletion before allogeneic stem cell transplantation.
- Published
- 2011
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40. Cyclophosphamide, fludarabine, alemtuzumab, and rituximab as salvage therapy for heavily pretreated patients with chronic lymphocytic leukemia.
- Author
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Badoux XC, Keating MJ, Wang X, O'Brien SM, Ferrajoli A, Faderl S, Burger J, Koller C, Lerner S, Kantarjian H, and Wierda WG
- Subjects
- Adult, Aged, Alemtuzumab, Antibodies, Monoclonal adverse effects, Antibodies, Monoclonal, Humanized, Antibodies, Monoclonal, Murine-Derived administration & dosage, Antibodies, Monoclonal, Murine-Derived adverse effects, Antibodies, Neoplasm administration & dosage, Antibodies, Neoplasm adverse effects, Chromosome Deletion, Chromosomes, Human, Pair 17, Combined Modality Therapy, Cyclophosphamide administration & dosage, Cyclophosphamide adverse effects, Disease-Free Survival, Humans, Infections etiology, Leukemia, Lymphocytic, Chronic, B-Cell genetics, Middle Aged, Rituximab, Salvage Therapy, Smith-Magenis Syndrome, Stem Cell Transplantation, Transplantation, Homologous, Vidarabine administration & dosage, Vidarabine adverse effects, Vidarabine analogs & derivatives, Antibodies, Monoclonal administration & dosage, Antineoplastic Combined Chemotherapy Protocols adverse effects, Leukemia, Lymphocytic, Chronic, B-Cell drug therapy, Leukemia, Lymphocytic, Chronic, B-Cell therapy
- Abstract
Patients with relapsed chronic lymphocytic leukemia (CLL) and high-risk features, such as fludarabine refractoriness, complex karyotype, or abnormalities of chromosome 17p, experience poor outcomes after standard fludaradine-based regimens. Alemtuzumab is a chimeric CD52 monoclonal antibody with activity in CLL patients with fludarabine-refractory disease and 17p deletion. We report the outcome for 80 relapsed or refractory patients with CLL enrolled in a phase 2 study of cyclophosphamide, fludarabine, alemtuzumab, and rituximab (CFAR). All patients were assessed for response and progression according to the 1996 CLL-working group criteria. For the intention-to-treat analysis, the overall response rate was 65%, including 29% complete response. The estimated progression-free survival was 10.6 months and median overall survival was 16.7 months. Although we noted higher complete response in high-risk patients after CFAR compared with a similar population who had received fludarabine, cyclophosphamide, and rituximab as salvage therapy, there was no significant improvement in progression-free survival and overall survival appeared worse. CFAR was associated with a high rate of infectious complications with 37 patients (46%) experiencing a serious infection during therapy and 28% of evaluable patients experiencing late serious infections. Although CFAR produced good response rates in this highly pretreated high-risk group of patients, there was no benefit in survival outcomes.
- Published
- 2011
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41. LDOC1 mRNA is differentially expressed in chronic lymphocytic leukemia and predicts overall survival in untreated patients.
- Author
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Duzkale H, Schweighofer CD, Coombes KR, Barron LL, Ferrajoli A, O'Brien S, Wierda WG, Pfeifer J, Majewski T, Czerniak BA, Jorgensen JL, Medeiros LJ, Freireich EJ, Keating MJ, and Abruzzo LV
- Subjects
- Alternative Splicing genetics, B-Lymphocytes physiology, Burkitt Lymphoma, HeLa Cells, Humans, Polymorphism, Single Nucleotide, Precursor Cell Lymphoblastic Leukemia-Lymphoma, Predictive Value of Tests, Prognosis, RNA, Messenger metabolism, Reverse Transcriptase Polymerase Chain Reaction, Risk Factors, Gene Expression Regulation, Leukemic physiology, Leukemia, Lymphocytic, Chronic, B-Cell genetics, Leukemia, Lymphocytic, Chronic, B-Cell mortality, Nuclear Proteins genetics, Tumor Suppressor Proteins genetics
- Abstract
We previously identified LDOC1 as one of the most significantly differentially expressed genes in untreated chronic lymphocytic leukemia (CLL) patients with respect to the somatic mutation status of the immunoglobulin heavy-chain variable region genes. However, little is known about the normal function of LDOC1, its contribution to the pathophysiology of CLL, or its prognostic significance. In this study, we have investigated LDOC1 mRNA expression in a large cohort of untreated CLL patients, as well as in normal peripheral blood B-cell (NBC) subsets and primary B-cell lymphoma samples. We have confirmed that LDOC1 is dramatically down-regulated in mutated CLL cases compared with unmutated cases, and have identified a new splice variant, LDOC1S. We show that LDOC1 is expressed in NBC subsets (naive > memory), suggesting that it may play a role in normal B-cell development. It is also expressed in primary B-cell lymphoma samples, in which its expression is associated with somatic mutation status. In CLL, we show that high levels of LDOC1 correlate with biomarkers of poor prognosis, including cytogenetic markers, unmutated somatic mutation status, and ZAP70 expression. Finally, we demonstrate that LDOC1 mRNA expression is an excellent predictor of overall survival in untreated CLL patients.
- Published
- 2011
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42. Fludarabine, cyclophosphamide, and rituximab chemoimmunotherapy is highly effective treatment for relapsed patients with CLL.
- Author
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Badoux XC, Keating MJ, Wang X, O'Brien SM, Ferrajoli A, Faderl S, Burger J, Koller C, Lerner S, Kantarjian H, and Wierda WG
- Subjects
- Antineoplastic Agents adverse effects, Antineoplastic Combined Chemotherapy Protocols adverse effects, Disease-Free Survival, Humans, Middle Aged, Multivariate Analysis, Neoplasm, Residual, Proportional Hazards Models, Recurrence, Rituximab, Time Factors, Treatment Outcome, Vidarabine therapeutic use, Antibodies, Monoclonal, Murine-Derived therapeutic use, Antineoplastic Agents therapeutic use, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Cyclophosphamide therapeutic use, Leukemia, Lymphocytic, Chronic, B-Cell drug therapy, Leukemia, Lymphocytic, Chronic, B-Cell prevention & control, Vidarabine analogs & derivatives
- Abstract
Optimal management of patients with relapsed/refractory chronic lymphocytic leukemia (CLL) is dictated by patient characteristics, prior therapy, and response to prior therapy. We report the final analysis of combined fludarabine, cyclophosphamide, and rituximab (FCR) for previously treated patients with CLL and identify patients who benefit most from this therapy. We explore efficacy of FCR in patients beyond first relapse, patients with prior exposure to fludarabine and alkylating agent combinations, and patients with prior exposure to rituximab. The FCR regimen was administered to 284 previously treated patients with CLL. Patients were assessed for response and progression by 1996 National Cancer Institute-Working Group (NCI-WG) criteria for CLL and followed for survival. The overall response rate was 74%, with 30% complete remission. The estimated median overall survival was 47 months and median progression-free survival for all patients was 21 months. Subgroup analyses indicated that the following patients were most suitable for FCR treatment: patients with up to 3 prior treatments, fludarabine-sensitive patients irrespective of prior rituximab exposure, and patients without chromosome 17 abnormalities. FCR is an active and well-tolerated therapy for patients with relapsed CLL. The addition of rituximab to FC improved quality and durability of response in this patient population.
- Published
- 2011
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43. CCL3 (MIP-1α) plasma levels and the risk for disease progression in chronic lymphocytic leukemia.
- Author
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Sivina M, Hartmann E, Kipps TJ, Rassenti L, Krupnik D, Lerner S, LaPushin R, Xiao L, Huang X, Werner L, Neuberg D, Kantarjian H, O'Brien S, Wierda WG, Keating MJ, Rosenwald A, and Burger JA
- Subjects
- Adult, Aged, Aged, 80 and over, Chemokine CCL4 blood, Disease Progression, Enzyme-Linked Immunosorbent Assay, Female, Flow Cytometry, Humans, Leukemia, Lymphocytic, Chronic, B-Cell pathology, Male, Middle Aged, Prognosis, Survival Rate, ZAP-70 Protein-Tyrosine Kinase blood, Biomarkers, Tumor blood, Chemokine CCL3 blood, Gene Expression Regulation, Leukemic, Leukemia, Lymphocytic, Chronic, B-Cell blood
- Abstract
B-cell receptor (BCR) signaling has been inferred as an important mechanism for disease progression in chronic lymphocytic leukemia (CLL) and other B-cell malignancies. In response to BCR activation, CLL cells secrete the chemokine CCL3, which fosters interactions between CLL cells and the leukemia microenvironment. CCL3 secretion correlates with expression of the 70-kDa ζ-associated protein (ZAP-70) and responsiveness of the CLL clone to BCR stimulation. Here, we measured CCL3 plasma levels by enzyme-linked immunosorbent assay (ELISA) in 351 CLL patients and examined CCL3 levels for associations with established prognostic markers and time from diagnosis to initial therapy. We found that CCL3 plasma concentrations were strongly associated with established prognostic markers. In a Cox proportional hazards regression model, CCL3 as well as established prognostic markers (immunoglobulin heavy chain variable-region mutation status, CD38 or ZAP-70 cytogenetics, clinical stage) were significantly associated with time to treatment. Multivariable analysis revealed that CCL3 (hazard ratio [HR] = 2.33, P < .0001), advanced clinical stage (HR = 2.75, P = .0025), poor risk cytogenetics (del 17p, HR = 2.38; del11q, HR = 2.36, P = .001), and CD38 expression (HR = 1.43, P = .023) were independent prognostic markers. Collectively, CCL3 is a novel, robust, and independent prognostic marker in CLL that can easily and reliably be measured by ELISA. CCL3 therefore should become useful for risk assessment in patients with CLL.
- Published
- 2011
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44. microRNA fingerprinting of CLL patients with chromosome 17p deletion identify a miR-21 score that stratifies early survival.
- Author
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Rossi S, Shimizu M, Barbarotto E, Nicoloso MS, Dimitri F, Sampath D, Fabbri M, Lerner S, Barron LL, Rassenti LZ, Jiang L, Xiao L, Hu J, Secchiero P, Zauli G, Volinia S, Negrini M, Wierda W, Kipps TJ, Plunkett W, Coombes KR, Abruzzo LV, Keating MJ, and Calin GA
- Subjects
- Adult, Aged, Aged, 80 and over, Female, Genetic Markers, Genetic Testing standards, Humans, In Situ Hybridization, Fluorescence, Kaplan-Meier Estimate, Karyotyping, Male, Middle Aged, Nucleotide Mapping, Predictive Value of Tests, Prognosis, Reproducibility of Results, Risk Factors, Chromosome Aberrations, Chromosomes, Human, Pair 17, Genetic Testing statistics & numerical data, Leukemia, Lymphocytic, Chronic, B-Cell genetics, Leukemia, Lymphocytic, Chronic, B-Cell mortality, MicroRNAs genetics
- Abstract
Aberrant expression of microRNAs (miRNAs) has been associated with clinical outcome in patients with chronic lymphocytic leukemia (CLL). To identify a powerful and easily assessable miRNA bio-marker of prognosis and survival, we performed quantitative reverse-transcription polymerase chain reaction (qRT-PCR) profiling in 104 CLL patients with a well-defined chromosome 17p status, and we validated our findings with miRNA microarray data from an independent cohort of 80 patients. We found that miR-15a, miR-21, miR-34a, miR-155, and miR-181b were differentially expressed between CLLs with chromosome 17p deletion and CLLs with normal 17p and normal karyotype, and that miR-181b was down-regulated in therapy-refractory cases. miR-21 expression levels were significantly higher in patients with poor prognosis and predicted overall survival (OS), and miR-181b expression levels significantly predicted treatment-free survival. We developed a 21FK score (miR-21 qRT-PCR, fluorescence in situ hybridization, Karyotype) to stratify patients according to OS and found that patients with a low score had a significantly longer OS time. When we evaluated the relative power of the 21FK score with the most used prognostic factors, the score was the most significant in both CLL cohorts. We conclude that the 21FK score represents a useful tool for distinguishing between good-prognosis and poor-prognosis CLL patients.
- Published
- 2010
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45. Phase 2 and pharmacodynamic study of oral forodesine in patients with advanced, fludarabine-treated chronic lymphocytic leukemia.
- Author
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Balakrishnan K, Verma D, O'Brien S, Kilpatrick JM, Chen Y, Tyler BF, Bickel S, Bantia S, Keating MJ, Kantarjian H, Gandhi V, and Ravandi F
- Subjects
- Administration, Oral, Aged, Antineoplastic Agents administration & dosage, Apoptosis drug effects, Drug Administration Schedule, Drug Therapy, Combination, Enzyme Inhibitors blood, Female, Follow-Up Studies, Humans, Leukemia, Lymphocytic, Chronic, B-Cell metabolism, Lymphocyte Count, Lymphocytes cytology, Lymphocytes drug effects, Male, Middle Aged, Phosphoric Monoester Hydrolases metabolism, Purine Nucleosides blood, Purine-Nucleoside Phosphorylase antagonists & inhibitors, Purine-Nucleoside Phosphorylase metabolism, Pyrimidinones blood, Severity of Illness Index, Vidarabine administration & dosage, Enzyme Inhibitors administration & dosage, Enzyme Inhibitors pharmacokinetics, Leukemia, Lymphocytic, Chronic, B-Cell drug therapy, Purine Nucleosides administration & dosage, Purine Nucleosides pharmacokinetics, Pyrimidinones administration & dosage, Pyrimidinones pharmacokinetics, Vidarabine analogs & derivatives
- Abstract
Forodesine is a new and potent purine nucleoside phosphorylase (PNP) inhibitor. Patients with chronic lymphocytic leukemia (CLL) with primary resistance to fludarabine-based therapy or with progressive disease were eligible for oral forodesine (200 mg/d) for up to 24 weeks. Eight patients with median lymphocyte count of 35.9 x 10(9)/L and median serum beta2 microglobulin level of 6.45 mg/L were treated. Six had Rai stage III to IV and were previously heavily treated (median prior therapy = 5). Two had transient decrease in lymphocyte count to normal, whereas in 5, disease progressed. Adverse events were mild. Steady-state level of forodesine ranged from 200 to 1300 nM and did not reach desired 2 microM level. PNP inhibition ranged from 57% to 89% and steady-state 2'-deoxyguanosine (dGuo) concentration median was 1.8 microM. Intracellular deoxyguanosine triphosphate (dGTP) increase was very modest, from median of 6 microM to 10 microM. Compared with in vivo, in vitro incubations of CLL lymphocytes with 10 or 20 microM dGuo and forodesine (2 microM) resulted in accumulation of higher levels of dGTP (40-250 microM) which resulted in increase in apoptosis. Forodesine has biologic activity in CLL; pharmacodynamic parameters suggest that an alternate dosing schedule and/or higher doses to achieve greater intracellular dGTP may be beneficial in this patient population.
- Published
- 2010
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46. STAT3 is constitutively phosphorylated on serine 727 residues, binds DNA, and activates transcription in CLL cells.
- Author
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Hazan-Halevy I, Harris D, Liu Z, Liu J, Li P, Chen X, Shanker S, Ferrajoli A, Keating MJ, and Estrov Z
- Subjects
- Active Transport, Cell Nucleus genetics, Aged, Aged, 80 and over, Apoptosis genetics, Cell Line, Tumor, Cell Nucleus genetics, Cell Proliferation, Cell Survival genetics, DNA, Neoplasm genetics, Female, Humans, Lentivirus, Leukemia, Lymphocytic, Chronic, B-Cell genetics, Leukemia, Lymphocytic, Chronic, B-Cell therapy, Male, Middle Aged, Neoplasm Proteins genetics, Phosphorylation genetics, STAT3 Transcription Factor genetics, Serine genetics, Serine metabolism, Cell Nucleus metabolism, DNA, Neoplasm metabolism, Leukemia, Lymphocytic, Chronic, B-Cell metabolism, Neoplasm Proteins metabolism, STAT3 Transcription Factor metabolism, Transcription, Genetic
- Abstract
Chronic lymphocytic leukemia (CLL) is the most common leukemia in the Western hemisphere, but its pathogenesis is still poorly understood. Constitutive tyrosine phosphorylation (p) of signal transducer and activator of transcription (STAT) 3 occurs in several solid tumors and hematologic malignancies. In CLL, however, STAT3 is constitutively phosphorylated on serine 727, not tyrosine 705, residues. Because the biologic significance of serine pSTAT3 in CLL is not known, we studied peripheral blood cells of 106 patients with CLL and found that, although tyrosine pSTAT3 was inducible, serine pSTAT3 was constitutive in all patients studied, regardless of blood count, disease stage, or treatment status. In addition, we demonstrated that constitutive serine pSTAT3 translocates to the nucleus by the karyopherin-beta nucleocytoplasmic system and binds DNA. Dephosphorylation of inducible tyrosine pSTAT3 did not affect STAT3-DNA binding, suggesting that constitutive serine pSTAT3 binds DNA. Furthermore, infection of CLL cells with lentiviral STAT3-small hairpin RNA reduced the expression of several STAT3-regulated survival and proliferation genes and induced apoptosis, suggesting that constitutive serine pSTAT3 initiates transcription in CLL cells. Taken together, our data suggest that constitutive phosphorylation of STAT3 on serine 727 residues is a hallmark of CLL and that STAT3 be considered a therapeutic target in this disease.
- Published
- 2010
- Full Text
- View/download PDF
47. High TCL1 levels are a marker of B-cell receptor pathway responsiveness and adverse outcome in chronic lymphocytic leukemia.
- Author
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Herling M, Patel KA, Weit N, Lilienthal N, Hallek M, Keating MJ, and Jones D
- Subjects
- Blotting, Western, Cells, Cultured, Flow Cytometry, Humans, Immunophenotyping, Kaplan-Meier Estimate, Leukemia, Lymphocytic, Chronic, B-Cell metabolism, Leukemia, Lymphocytic, Chronic, B-Cell mortality, Microscopy, Confocal, Proto-Oncogene Mas, Proto-Oncogene Proteins c-akt metabolism, Biomarkers, Tumor analysis, Leukemia, Lymphocytic, Chronic, B-Cell pathology, Proto-Oncogene Proteins biosynthesis, Receptors, Antigen, B-Cell metabolism, Signal Transduction immunology
- Abstract
Although activation of the B-cell receptor (BCR) signaling pathway is implicated in the pathogenesis of chronic lymphocytic leukemia (CLL), its clinical impact and the molecular correlates of such response are not clearly defined. T-cell leukemia 1 (TCL1), the AKT modulator and proto-oncogene, is differentially expressed in CLL and linked to its pathogenesis based on CD5(+) B-cell expansions arising in TCL1-transgenic mice. We studied here the association of TCL1 levels and its intracellular dynamics with the in vitro responses to BCR stimulation in 70 CLL cases. The growth kinetics after BCR engagement correlated strongly with the degree and timing of induced AKT phospho-activation. This signaling intensity was best predicted by TCL1 levels and the kinetics of TCL1-AKT corecruitment to BCR membrane activation complexes, which further included the kinases LYN, SYK, ZAP70, and PKC. High TCL1 levels were also strongly associated with aggressive disease features, such as advanced clinical stage, higher white blood cell counts, and shorter lymphocyte doubling time. Higher TCL1 levels independently predicted an inferior clinical outcome (ie, shorter progression-free survival, P < .001), regardless of therapy regimen, especially for ZAP70(+) tumors. We propose TCL1 as a marker of the BCR-responsive CLL subset identifying poor prognostic cases where targeting BCR-associated kinases may be therapeutically useful.
- Published
- 2009
- Full Text
- View/download PDF
48. Diverse marrow stromal cells protect CLL cells from spontaneous and drug-induced apoptosis: development of a reliable and reproducible system to assess stromal cell adhesion-mediated drug resistance.
- Author
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Kurtova AV, Balakrishnan K, Chen R, Ding W, Schnabl S, Quiroga MP, Sivina M, Wierda WG, Estrov Z, Keating MJ, Shehata M, Jäger U, Gandhi V, Kay NE, Plunkett W, and Burger JA
- Subjects
- Animals, Antineoplastic Agents pharmacology, Apoptosis drug effects, Apoptosis physiology, Blotting, Western, Bone Marrow Cells cytology, Bone Marrow Cells drug effects, Cell Adhesion physiology, Cell Line, Tumor, Cells, Cultured, Coculture Techniques, Flow Cytometry, Humans, Leukemia, Lymphocytic, Chronic, B-Cell pathology, Mice, Stromal Cells cytology, Stromal Cells drug effects, Bone Marrow Cells metabolism, Cell Communication physiology, Drug Resistance, Neoplasm, Leukemia, Lymphocytic, Chronic, B-Cell metabolism, Stromal Cells metabolism
- Abstract
Marrow stromal cells (MSCs) provide important survival and drug resistance signals to chronic lymphocytic leukemia (CLL) cells, but current models to analyze CLL-MSC interactions are heterogeneous. Therefore, we tested different human and murine MSC lines and primary human MSCs for their ability to protect CLL cells from spontaneous and drug-induced apoptosis. Our results show that both human and murine MSCs are equally effective in protecting CLL cells from fludarabine-induced apoptosis. This protective effect was sustained over a wide range of CLL-MSC ratios (5:1 to 100:1), and the levels of protection were reproducible in 4 different laboratories. Human and murine MSCs also protected CLL cells from dexamethasone- and cyclophosphamide-induced apoptosis. This protection required cell-cell contact and was virtually absent when CLL cells were separated from the MSCs by micropore filters. Furthermore, MSCs maintained Mcl-1 and protected CLL cells from spontaneous and fludarabine-induced Mcl-1 and PARP cleavage. Collectively, these studies define common denominators for CLL cocultures with MSCs. They also provide a reliable, validated tool for future investigations into the mechanism of MSC-CLL cross talk and for drug testing in a more relevant fashion than the commonly used suspension cultures.
- Published
- 2009
- Full Text
- View/download PDF
49. De novo deletion 17p13.1 chronic lymphocytic leukemia shows significant clinical heterogeneity: the M. D. Anderson and Mayo Clinic experience.
- Author
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Tam CS, Shanafelt TD, Wierda WG, Abruzzo LV, Van Dyke DL, O'Brien S, Ferrajoli A, Lerner SA, Lynn A, Kay NE, and Keating MJ
- Subjects
- Adult, Aged, Aged, 80 and over, Alemtuzumab, Antibodies, Monoclonal administration & dosage, Antibodies, Monoclonal therapeutic use, Antibodies, Monoclonal, Humanized, Antibodies, Monoclonal, Murine-Derived, Antibodies, Neoplasm administration & dosage, Antibodies, Neoplasm therapeutic use, Antimetabolites, Antineoplastic administration & dosage, Antineoplastic Combined Chemotherapy Protocols administration & dosage, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Chromosomes, Human, Pair 17 genetics, Disease Progression, Female, Humans, In Situ Hybridization, Fluorescence, Leukemia, Lymphocytic, Chronic, B-Cell drug therapy, Leukemia, Lymphocytic, Chronic, B-Cell mortality, Male, Middle Aged, Prognosis, Retrospective Studies, Rituximab, Survival Rate, Treatment Outcome, Chromosome Deletion, Chromosomes, Human, Pair 17 ultrastructure, Leukemia, Lymphocytic, Chronic, B-Cell genetics
- Abstract
To determine the clinical fate of patients with de novo deletion 17p13.1 (17p-) chronic lymphocytic leukemia (CLL), we retrospectively studied the outcome of 99 treatment-naive 17p- CLL patients from the M. D. Anderson Cancer Center (n = 64) and the Mayo Clinic (n = 35). Among 67 asymptomatic patients followed for progression, 53% developed CLL requiring treatment over 3 years. Patients who had not progressed by 18 months subsequently had stable disease, with 3 of 19 patients progressing after follow-up of up to 70 months. Risk factors for progressive disease were Rai stage of 1 or higher and unmutated immunoglobulin variable region heavy chain (IgVH). The overall survival rate was 65% at 3 years. Rai stage 1 or higher, unmutated IgVH, and 17p- in 25% or more of nuclei were adverse factors for survival. The 3-year survival rates of patients with 1 or fewer, 2, and 3 of these factors were 95%, 74%, and 22%, respectively (P < .001). Response rates to therapy with rituximab (n = 6); purine analogues and rituximab (n = 25); and purine analogues, rituximab, and alemtuzumab (n = 16) combinations were 50%, 72%, and 81%, respectively. Patients with 17p- CLL exhibit clinical heterogeneity, with some patients experiencing an indolent course. Survival can be predicted using clinical and biologic characteristics.
- Published
- 2009
- Full Text
- View/download PDF
50. B-cell antigen receptor signaling enhances chronic lymphocytic leukemia cell migration and survival: specific targeting with a novel spleen tyrosine kinase inhibitor, R406.
- Author
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Quiroga MP, Balakrishnan K, Kurtova AV, Sivina M, Keating MJ, Wierda WG, Gandhi V, and Burger JA
- Subjects
- Adult, Aged, Aged, 80 and over, Animals, Cell Adhesion Molecules biosynthesis, Cell Adhesion Molecules genetics, Cell Survival drug effects, Cell Survival physiology, Chemokine CCL3 metabolism, Chemokine CCL4 metabolism, Chemotaxis drug effects, Chemotaxis physiology, Coculture Techniques, Drug Screening Assays, Antitumor, Female, Humans, Intracellular Signaling Peptides and Proteins physiology, Leukemia, Lymphocytic, Chronic, B-Cell enzymology, Male, Mice, Middle Aged, Neoplasm Proteins metabolism, Neoplasm Proteins physiology, Protein Processing, Post-Translational drug effects, Protein-Tyrosine Kinases physiology, Receptors, Chemokine biosynthesis, Receptors, Chemokine genetics, Stromal Cells physiology, Syk Kinase, Antineoplastic Agents pharmacology, Intracellular Signaling Peptides and Proteins antagonists & inhibitors, Leukemia, Lymphocytic, Chronic, B-Cell pathology, Lymphocyte Activation drug effects, Neoplasm Proteins antagonists & inhibitors, Oxazines pharmacology, Protein Kinase Inhibitors pharmacology, Protein-Tyrosine Kinases antagonists & inhibitors, Pyridines pharmacology, Receptors, Antigen, B-Cell physiology, Signal Transduction drug effects
- Abstract
Antigenic stimulation through the B-cell antigen receptor (BCR) is considered to promote the expansion of chronic lymphocytic leukemia (CLL) B cells. The spleen tyrosine kinase (Syk), a key component of BCR signaling, can be blocked by R406, a small-molecule Syk inhibitor, that displayed activity in CLL patients in a first clinical trial. In this study, we investigated the effects of BCR stimulation and R406 on CLL cell survival and migration. The prosurvival effects promoted by anti-IgM stimulation and nurselike cells were abrogated by R406. BCR triggering up-regulated adhesion molecules, and increased CLL cell migration toward the chemokines CXCL12 and CXCL13. BCR activation also enhanced CLL cell migration beneath marrow stromal cells. These responses were blocked by R406, which furthermore abrogated BCR-dependent secretion of T-cell chemokines (CCL3 and CCL4) by CLL cells. Finally, R406 inhibited constitutive and BCR-induced activation of Syk, extracellular signal-regulated kinases, and AKT, and blocked BCR-induced calcium mobilization. These findings suggest that BCR activation favors CLL cell homing, retention, and survival in tissue microenvironments. R406 effectively blocks these BCR-dependent responses in CLL cells, providing an explanation for the activity of R406 in patients with CLL.
- Published
- 2009
- Full Text
- View/download PDF
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