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1.
Blood ; 139(8): 1198-1207, 2022 02 24.
Article in English | MEDLINE | ID: mdl-34469514

ABSTRACT

The BCL2 inhibitor venetoclax has established therapeutic roles in chronic lymphocytic leukemia (CLL) and acute myeloid leukemia (AML). As BCL2 is an important determinant of survival of both myeloid progenitor and B cells, we investigated whether clinical and molecular abnormalities arise in the myeloid compartment during long-term continuous venetoclax treatment of CLL in 89 patients (87 with relapsed/refractory CLL). Over a median follow-up of 75 (range 21-98) months, persistent cytopenias (≥1 of neutropenia, thrombocytopenia, anemia) lasting ≥4 months and unrelated to CLL occurred in 25 patients (28%). Of these patients, 20 (80%) displayed clonal hematopoiesis, including 10 with therapy-related myeloid neoplasms (t-MNs). t-MNs occurred exclusively in patients previously exposed to fludarabine-alkylator combination therapy with a cumulative 5-year incidence of 10.4% after venetoclax initiation, consistent with rates reported for patients exposed to fludarabine-alkylator combination therapy without venetoclax. To determine whether the altered myelopoiesis reflected the acquisition of mutations, we analyzed samples from patients with no or minimal bone marrow CLL burden (n = 41). Mutations in the apoptosis effector BAX were identified in 32% (13/41). In cellular assays, C-terminal BAX mutants abrogated outer mitochondrial membrane localization of BAX and engendered resistance to venetoclax killing. BAX-mutated clonal hematopoiesis occurred independently of prior fludarabine-alkylator combination therapy exposure and was not associated with t-MNs. Single-cell sequencing revealed clonal co-occurrence of mutations in BAX with DNMT3A or ASXL1. We also observed simultaneous BCL2 mutations within CLL cells and BAX mutations in the myeloid compartment of the same patients, indicating lineage-specific adaptation to venetoclax therapy.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Bridged Bicyclo Compounds, Heterocyclic , Hematologic Neoplasms , Leukemia, Lymphocytic, Chronic, B-Cell , Mutation , Myelopoiesis/drug effects , Myeloproliferative Disorders , Neoplasms, Second Primary , Sulfonamides , bcl-2-Associated X Protein , Aged , Aged, 80 and over , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Bridged Bicyclo Compounds, Heterocyclic/administration & dosage , Bridged Bicyclo Compounds, Heterocyclic/adverse effects , Female , Hematologic Neoplasms/genetics , Hematologic Neoplasms/metabolism , Humans , Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy , Leukemia, Lymphocytic, Chronic, B-Cell/genetics , Leukemia, Lymphocytic, Chronic, B-Cell/metabolism , Male , Middle Aged , Myeloproliferative Disorders/genetics , Myeloproliferative Disorders/metabolism , Neoplasms, Second Primary/genetics , Neoplasms, Second Primary/metabolism , Sulfonamides/administration & dosage , Sulfonamides/adverse effects , Vidarabine/administration & dosage , Vidarabine/adverse effects , Vidarabine/analogs & derivatives , bcl-2-Associated X Protein/antagonists & inhibitors , bcl-2-Associated X Protein/genetics , bcl-2-Associated X Protein/metabolism
2.
Leuk Lymphoma ; 57(5): 1044-53, 2016 May.
Article in English | MEDLINE | ID: mdl-26464106

ABSTRACT

Despite its efficacy in prospective trials, full dose fludarabine, cyclophosphamide and rituximab (FCR) may be too toxic for elderly patients with chronic lymphocytic leukemia (CLL) in clinical practice. We retrospectively reviewed the impact of dose reductions in FCR therapy on the outcomes of 42 consecutive patients aged 65-87 (median 72) years. Despite a median cumulative fludarabine dose reduction of 50% from full dose, the objective response and complete response rates were 86% and 38% respectively (frontline 94%/59%; previously treated 80%/24%). Dose reductions of 25-75% were not significantly associated with inferior progression free survival compared to minimal reductions (≤25%) (p=0.49), and did not preclude deep responses, including six cases (14%) of minimal residual disease negativity. Although hematological and infectious toxicities were common, treatment limiting adverse effects were infrequent. Dose attenuated FCR appears to have preserved efficacy and may be a viable therapeutic option for elderly patients with CLL.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy , Age Factors , Aged , Aged, 80 and over , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Cyclophosphamide/administration & dosage , Female , Humans , Leukemia, Lymphocytic, Chronic, B-Cell/mortality , Leukemia, Lymphocytic, Chronic, B-Cell/pathology , Male , Neoplasm Staging , Rituximab/administration & dosage , Treatment Outcome , Vidarabine/administration & dosage , Vidarabine/analogs & derivatives
3.
Br J Haematol ; 170(5): 669-78, 2015 Sep.
Article in English | MEDLINE | ID: mdl-25942994

ABSTRACT

The oral BCL2 inhibitor navitoclax has moderate single-agent efficacy in chronic lymphocytic leukaemia (CLL) and minor activity in lymphoma in Phase 1 trials. Navitoclax synergizes with rituximab in preclinical models of B-cell lymphoid cancers. We report the safety, pharmacokinetics and clinical activity of this combination. Patients received navitoclax (200-325 mg) daily and four standard weekly doses of rituximab. Twenty-nine patients were enrolled across three dose-escalation cohorts and a safety expansion cohort (250 mg/d navitoclax). The combination was well tolerated. Common toxicities were mild diarrhoea (79%) and nausea (72%). Grade 4 thrombocytopenia occurred in 17% of patients (dose limiting at 325 mg/d). CD19(+) counts were severely reduced, while CD3(+) cells (~ 20%) and serum immunoglobulin M levels (~ 33%) were also reduced during the first year. The maximum tolerated dose for navitoclax in combination was 250 mg/d. Pharmacokinetic analyses revealed no apparent interactions between the drugs. The response rate in patients with follicular lymphoma was 9/12, including five complete responses. All five patients with CLL/small lymphocytic leukaemia achieved partial responses. One of nine patients with aggressive lymphoma responded. The addition of rituximab to navitoclax 250 mg/d is safe; the combination demonstrates higher response rates for low-grade lymphoid cancers than observed for either agent alone in previous Phase 1 trials.


Subject(s)
Antigens, CD20 , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/pharmacokinetics , Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy , Lymphoma, Follicular/drug therapy , Proto-Oncogene Proteins c-bcl-2/antagonists & inhibitors , Adult , Aged , Aged, 80 and over , Aniline Compounds/administration & dosage , Aniline Compounds/adverse effects , Aniline Compounds/pharmacokinetics , Antibodies, Monoclonal, Murine-Derived/administration & dosage , Antibodies, Monoclonal, Murine-Derived/adverse effects , Antibodies, Monoclonal, Murine-Derived/pharmacokinetics , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Female , Humans , Leukemia, Lymphocytic, Chronic, B-Cell/blood , Lymphoma, Follicular/blood , Male , Middle Aged , Rituximab , Sulfonamides/administration & dosage , Sulfonamides/adverse effects , Sulfonamides/pharmacokinetics
4.
Leuk Lymphoma ; 56(1): 49-56, 2015 Jan.
Article in English | MEDLINE | ID: mdl-24724780

ABSTRACT

There are limited data regarding the role of (18)F-fluorodeoxyglucose positron emission tomography with computed tomography (FDG PET-CT) scanning in primary mediastinal B-cell lymphoma (PMBL). We analyzed 28 patients with PMBL treated with chemotherapy, of whom 25 (89%) also received rituximab and 17 (61%) radiotherapy. PET-CT scans were interpreted using visual analysis and a 5-point scale. After a median follow-up of 2.6 years, four patients relapsed and two died. The 2-year progression-free survival and overall survival were 86% and 94%. PET-CT has excellent negative predictive value (interim, 86-87%; end of treatment, 95%) but limited positive predictive value due to the high frequency of positive scans. Several patients with persistent metabolically active masses underwent biopsies, which showed necrosis but no lymphoma. Thus a negative PET-CT is an excellent predictor of subsequent outcome. However, residual metabolically active masses after treatment should be biopsied to confirm viable lymphoma prior to salvage therapy.


Subject(s)
Fluorodeoxyglucose F18 , Lymphoma, B-Cell/diagnosis , Mediastinal Neoplasms/diagnosis , Positron-Emission Tomography , Tomography, X-Ray Computed , Adolescent , Adult , Aged , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Female , Humans , Image Interpretation, Computer-Assisted , Lymphoma, B-Cell/mortality , Lymphoma, B-Cell/therapy , Male , Mediastinal Neoplasms/mortality , Mediastinal Neoplasms/therapy , Middle Aged , Neoplasm Recurrence, Local , Patient Outcome Assessment , Prognosis , Radiotherapy , Retrospective Studies , Young Adult
5.
Biol Blood Marrow Transplant ; 20(11): 1813-8, 2014 Nov.
Article in English | MEDLINE | ID: mdl-25042735

ABSTRACT

The role of allogeneic (allo-) and autologous stem cell transplantation (auto-SCT) in the management of patients with transformed indolent nonfollicular non-Hodgkin lymphoma is unknown. This is a multicenter, retrospective cohort study of patients with biopsy-proven indolent B cell nonfollicular non-Hodgkin lymphoma and simultaneous or subsequent biopsy-proven aggressive histology transformation who were treated with allo-SCT or auto-SCT between 1996 and 2013. All patients received myeloablative conditioning regimens. Outcomes were compared with a cohort of 246 patients with transformed follicular lymphoma who also underwent allo-SCT (n = 47) or auto-SCT (n = 199) across the same institutions and time frame. Thirty-four patients were identified with the following underlying indolent histologies: 15 (44%) marginal zone lymphoma, 11 (32%) chronic lymphocytic leukemia, 6 (18%) small lymphocytic lymphoma, and 2 (6%) lymphoplasmacytic lymphoma. Patients received various anthracycline or platinum-containing chemotherapy regimens for transformation, incorporating rituximab in 25 (74%). Twelve (35%) subsequently underwent allo-SCT, whereas 33 (65%) underwent auto-SCT. The 3-year overall survival rate after transplantation was 67% (allo-SCT 54%, auto-SCT 74%), and 3-year progression-free survival rate was 49% (allo-SCT 40%, auto-SCT 54%). The 3-year nonrelapse mortality rate was 14% (allo-SCT 15%, auto-SCT 7%). Transplant-related mortality at 100 days was 17% for allo-SCT and 0% for auto-SCT. Adjusted for type of stem cell transplantation, 3-year overall survival, progression-free survival, and nonrelapse mortality rates were similar to those of patients with transformed follicular lymphoma receiving allo-SCT and auto-SCT (P = .38, P = .69, and P = .54, respectively). Allo-SCT and auto-SCT may be reasonable treatments for selected patients with transformed nonfollicular indolent lymphoma, although medium-term outcomes and toxicity appear to be more favorable with auto-SCT.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Hematopoietic Stem Cell Transplantation/methods , Lymphoma, B-Cell/therapy , Adult , Aged , Anthracyclines/administration & dosage , Antibodies, Monoclonal, Murine-Derived/administration & dosage , Cohort Studies , Combined Modality Therapy , Disease-Free Survival , Female , Humans , Lymphoma, B-Cell/drug therapy , Male , Middle Aged , Organoplatinum Compounds/administration & dosage , Retrospective Studies , Rituximab , Survival Rate , Transplantation Conditioning , Treatment Outcome
6.
Ann Hematol ; 93(7): 1193-200, 2014 Jul.
Article in English | MEDLINE | ID: mdl-24595733

ABSTRACT

The optimum follow-up of patients with transformed indolent lymphoma (TrIL) is not well defined. We sought to determine the utility of surveillance positron emission tomography-computed tomography (PET-CT) in patients with TrIL achieving complete metabolic remission (CMR) after primary therapy. We performed a retrospective analysis of patients with TrIL treated at Peter MacCallum Cancer Centre between 2002 and 2012 who achieved CMR after primary therapy who had ≥1 subsequent surveillance PET-CT. Of 55 patients with TrIL, 37 (67 %) received autologous stem cell transplantation as consolidation following chemoimmunotherapy. After a median follow-up of 34 (range 3-101) months, the actuarial 3-year progression-free (PFS) and overall survival (OS) were 77 % (95 %CI 62-86 %) and 88 % (75-94 %), respectively. Of 180 surveillance PET-CT scans, there were 153 true negatives, 4 false positives, 1 false negative, 7 indeterminate and 15 true positives. Considering indeterminate scans as false positives, the specificity of PET-CT for detecting relapse was 94 %, sensitivity was 83 %, positive predictive value was 63 % and negative predictive value was 98 %. All seven subclinical (PET detected) relapses were of low-grade histology; in contrast, all nine relapses with diffuse large B cell lymphoma (DLBCL) were symptomatic. In our cohort of patients with TrIL achieving CMR, PET-CT detected subclinical low-grade relapses but all DLBCL relapses were accompanied by clinical symptoms. Thus, surveillance imaging of patients with TrIL achieving CMR is of limited clinical benefit. PET-CT should be reserved for evaluation of clinically suspected relapse.


Subject(s)
Cell Transformation, Neoplastic/pathology , Lymphoma/diagnostic imaging , Positron-Emission Tomography , Tomography, X-Ray Computed , Adult , Aged , Aged, 80 and over , Disease-Free Survival , Female , Follow-Up Studies , Humans , Lymphoma/pathology , Male , Middle Aged , Multimodal Imaging/methods , Neoplasm Recurrence, Local/diagnostic imaging , Neoplasm Recurrence, Local/pathology , Positron-Emission Tomography/methods , Remission Induction/methods , Retrospective Studies , Tomography, X-Ray Computed/methods , Treatment Outcome
7.
Front Oncol ; 3: 124, 2013.
Article in English | MEDLINE | ID: mdl-23730625

ABSTRACT

The tumor suppressor function of the promyelocytic leukemia (PML) protein was first identified as a result of its dysregulation in acute promyelocytic leukemia, however, its importance is now emerging far beyond hematological neoplasms, to an extensive range of malignancies, including solid tumors. In response to stress signals, PML coordinates the regulation of numerous proteins, which activate fundamental cellular processes that suppress tumorigenesis. Importantly, PML itself is the subject of specific post-translational modifications, including ubiquitination, phosphorylation, acetylation, and SUMOylation, which in turn control PML activity and stability and ultimately dictate cellular fate. Improved understanding of the regulation of this key tumor suppressor is uncovering potential opportunities for therapeutic intervention. Targeting the key negative regulators of PML in cancer cells such as casein kinase 2, big MAP kinase 1, and E6-associated protein, with specific inhibitors that are becoming available, provides unique and exciting avenues for restoring tumor suppression through the induction of apoptosis and senescence. These approaches could be combined with DNA damaging drugs and cytokines that are known to activate PML. Depending on the cellular context, reactivation or enhancement of tumor suppressive PML functions, or targeted elimination of aberrantly functioning PML, may provide clinical benefit.

9.
J Clin Oncol ; 30(5): 488-96, 2012 Feb 10.
Article in English | MEDLINE | ID: mdl-22184378

ABSTRACT

PURPOSE: BCL2 overexpression is a hallmark of chronic lymphocytic leukemia (CLL). The novel BH3 mimetic navitoclax (ABT-263) specifically inhibits BCL2 and related proteins BCL-x(l) and BCL-w, potently inducing apoptosis of CLL cells in vitro. A phase I trial in patients with CLL was conducted to evaluate the safety, pharmacokinetics, and biologic activity of oral navitoclax. PATIENTS AND METHODS: Twenty-nine patients with relapsed or refractory CLL received daily navitoclax for 14 days (10, 110, 200, or 250 mg/d; n = 15) or 21 days (125, 200, 250, or 300 mg/d; n = 14) of each 21-day cycle. Dose escalation decisions were informed by continual reassessment methodology. RESULTS: Lymphocytosis was reduced by more than 50% in 19 of 21 patients with baseline lymphocytosis. Among 26 patients treated with navitoclax ≥ 110 mg/d, nine (35%) achieved a partial response and seven maintained stable disease for more than 6 months. Median treatment duration was 7 months (range, 1 to ≥ 29 months). Median progression-free survival was 25 months. Activity was observed in patients with fludarabine-refractory disease, bulky adenopathy, and del(17p) CLL. Thrombocytopenia due to BCL-x(l) inhibition was the major dose-limiting toxicity and was dose-related. Low MCL1 expression and high BIM:MCL1 or BIM:BCL2 ratios in leukemic cells correlated with response. We determined that the navitoclax dose of 250 mg/d in a continuous dosing schedule was optimal for phase II studies. CONCLUSION: BCL2 is a valid therapeutic target in CLL, and its inhibition by navitoclax warrants further evaluation as monotherapy and in combination in this disease.


Subject(s)
Aniline Compounds/administration & dosage , Aniline Compounds/pharmacology , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/pharmacology , Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy , Proto-Oncogene Proteins c-bcl-2/antagonists & inhibitors , Proto-Oncogene Proteins c-bcl-2/metabolism , Sulfonamides/administration & dosage , Sulfonamides/pharmacology , Administration, Oral , Aged , Aniline Compounds/adverse effects , Aniline Compounds/pharmacokinetics , Antineoplastic Agents/adverse effects , Antineoplastic Agents/pharmacokinetics , Apoptosis Regulatory Proteins/metabolism , Bcl-2-Like Protein 11 , Biomarkers, Tumor/metabolism , Chromosome Deletion , Drug Administration Schedule , Female , Gene Expression Regulation, Neoplastic , Humans , In Situ Hybridization, Fluorescence , Leukemia, Lymphocytic, Chronic, B-Cell/genetics , Leukemia, Lymphocytic, Chronic, B-Cell/metabolism , Male , Membrane Proteins/metabolism , Middle Aged , Myeloid Cell Leukemia Sequence 1 Protein , Proto-Oncogene Proteins/metabolism , Sulfonamides/adverse effects , Sulfonamides/pharmacokinetics , Thrombocytopenia/chemically induced , Treatment Outcome
10.
Hematol Oncol ; 30(4): 170-4, 2012 Dec.
Article in English | MEDLINE | ID: mdl-22144117

ABSTRACT

Although multiple myeloma (MM) remains an incurable disease, considerable improvements in survival have been made with the introduction of autologous stem cell transplantation and new drugs. Central nervous system (CNS) MM is a rare complication associated with poor survival. Historically, CNS disease developed early in the course of MM; however recently, patients often present with CNS disease following multiple lines of therapy. It is hypothesized that exposure to novel agents (thalidomide, lenalidomide and bortezomib) changes the natural history of MM, increasing the lifetime risk of CNS disease. We analysed the baseline characteristics, treatment and outcome data of patients who presented with CNS MM at Peter MacCallum Cancer Centre between 2001 and 2010. Seven patients were identified, from 2005 onwards. All patients were Durie-Salmon stage IIIA or IIIB and International Staging System Scores I to III at baseline. All had received at least three lines of therapy, including high-dose chemotherapy with autologous stem cell transplantation and a novel agent, prior to developing CNS MM. Median time from diagnosis to CNS disease was 24 months (range 10-42). All patients died after developing CNS disease with median survival post-CNS disease of 2 months (range 1-23). The incidence of CNS MM is increasing, and time to development of CNS manifestations is prolonging, associated with increased use of high-dose chemotherapy and novel agents. Whether this is due to improved overall survival or specific characteristics of these therapies is not clear. Despite the availability of novel agents, survival after CNS MM remains poor.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/adverse effects , Central Nervous System Neoplasms/etiology , Multiple Myeloma/complications , Stem Cell Transplantation/adverse effects , Adult , Aged , Boronic Acids/administration & dosage , Bortezomib , Central Nervous System Neoplasms/diagnosis , Central Nervous System Neoplasms/mortality , Combined Modality Therapy , Humans , Lenalidomide , Middle Aged , Multiple Myeloma/mortality , Multiple Myeloma/therapy , Prognosis , Pyrazines/administration & dosage , Survival Rate , Thalidomide/administration & dosage , Thalidomide/analogs & derivatives , Transplantation, Autologous
15.
Br J Haematol ; 147(1): 83-8, 2009 Oct.
Article in English | MEDLINE | ID: mdl-19694718

ABSTRACT

Reported rates of central nervous system (CNS) involvement in mantle cell lymphoma (MCL) are highly variable but substantial (4-26%). Data is lacking regarding risk factors for CNS relapse, and for those patients in whom CNS prophylaxis could be beneficial. We present single institution retrospective analysis of data of baseline features, clinical course, rate of CNS disease and putative risk factors in 62 patients with MCL (18 female, 44 male). CNS disease (all cases were symptomatic) occurred in four patients at a median of 12 months (range 1-58) from diagnosis, with a crude incidence of 6.5% and 5-year actuarial incidence of 5 +/- 3%. Two cases had blastic MCL at diagnosis. Survival after CNS relapse ranged from 2-9 months. Patients who developed CNS disease had a significantly shorter survival from diagnosis than those who did not (P = 0.0024). Symptomatic CNS disease in patients with MCL either at presentation or relapse is an uncommon but devastating complication. In younger patients, more aggressive immuno-chemotherapy regimens containing CNS-penetrating agents may reduce the incidence of CNS disease. While not routinely justified for all patients, CNS prophylaxis may particularly benefit patients with blastic histology at diagnosis, or those with systemic relapse after first-line treatment.


Subject(s)
Central Nervous System Neoplasms/drug therapy , Lymphoma, Mantle-Cell/drug therapy , Adult , Aged , Aged, 80 and over , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Central Nervous System Neoplasms/pathology , Central Nervous System Neoplasms/prevention & control , Epidemiologic Methods , Female , Humans , Lymphoma, Mantle-Cell/pathology , Male , Middle Aged , Neoplasm Staging , Prognosis , Recurrence , Risk Factors , Treatment Outcome
17.
J Hematol Oncol ; 1: 10, 2008 Jul 29.
Article in English | MEDLINE | ID: mdl-18664261

ABSTRACT

BACKGROUND: Molecular characterisation of normal karyotype acute myeloid leukemia (NK-AML) allows prognostic stratification and potentially can alter treatment choices and pathways. Approximately 45-60% of patients with NK-AML carry NPM1 gene mutations and are associated with a favourable clinical outcome when FLT3-internal tandem duplications (ITD) are absent. High resolution melting (HRM) is a novel screening method that enables rapid identification of mutation positive DNA samples. RESULTS: We developed HRM assays to detect NPM1 mutations and FLT3-ITD and tested diagnostic samples from 44 NK-AML patients. Eight were NPM1 mutation positive only, 4 were both NPM1 mutation and FLT3-ITD positive and 4 were FLT3-ITD positive only. A novel point mutation Y572C (c.1715A>G) in exon 14 of FLT3 was also detected. In the group with de novo NK-AML, 40% (12/29) were NPM1 mutation positive whereas NPM1 mutations were observed in 20% (3/15) of secondary NK-AML cases. Sequencing was performed and demonstrated 100% concordance with the HRM results. CONCLUSION: HRM is a rapid and efficient method of screening NK-AML samples for both novel and known NPM1 and FLT3 mutations. NPM1 mutations can be observed in both primary and secondary NK-AML cases.


Subject(s)
Genetic Testing/methods , Mutation , Nuclear Proteins/genetics , fms-Like Tyrosine Kinase 3/genetics , Adult , Aged , Aged, 80 and over , Female , Gene Duplication , Genetic Testing/economics , Humans , Leukemia, Myeloid, Acute/genetics , Male , Middle Aged , Nucleophosmin , Time Factors , Young Adult
18.
J Natl Cancer Inst ; 97(23): 1781-5, 2005 Dec 07.
Article in English | MEDLINE | ID: mdl-16333034

ABSTRACT

The naturally occurring compound 3beta,16beta,17alpha-trihydroxycholest-5-en-22-one 16-O-(2-O-4-methoxybenzoyl-beta-D-xylopyranosyl)-(1-->3)-(2-O-acetyl-alpha-L-arabinopyranoside) (OSW-1) is found in the bulbs of Ornithogalum saudersiae and is highly cytotoxic against tumor cell lines. Using various human cancer and nonmalignant cell lines, we investigated the anticancer activity and selectivity of OSW-1 and its underlying mechanisms of action. OSW-1 exhibited extremely potent cytotoxic activity against cancer cells in vitro. Nonmalignant cells were statistically significantly less sensitive to OSW-1 than cancer cells, with concentrations that cause a 50% loss of cell viability 40-150-fold greater than those observed in malignant cells. Electron microscopy and biochemical analyses revealed that OSW-1 damaged the mitochondrial membrane and cristae in both human leukemia and pancreatic cancer cells, leading to the loss of transmembrane potential, increase of cytosolic calcium, and activation of calcium-dependent apoptosis. Clones of leukemia cells with mitochondrial DNA defects and respiration deficiency that had adapted the ability to survive in culture without mitochondrial respiration also were resistant to OSW-1. In vitro analysis revealed that OSW-1 effectively killed primary leukemia cells from chronic lymphocytic leukemia patients with disease refractory to fludarabine. The promising anticancer activity of OSW-1 and its unique mechanism of action make this compound worthy of further investigation for its potential to overcome drug resistance.


Subject(s)
Antineoplastic Agents/pharmacology , Apoptosis/drug effects , Cholestenones/pharmacology , Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy , Mitochondrial Membranes/drug effects , Saponins/pharmacology , Calcium Channels/metabolism , Cell Line, Tumor , Drug Resistance, Neoplasm , Humans , Inhibitory Concentration 50 , Microscopy, Electron , Vidarabine/analogs & derivatives , Vidarabine/pharmacology
19.
Curr Treat Options Oncol ; 6(3): 215-25, 2005 May.
Article in English | MEDLINE | ID: mdl-15869733

ABSTRACT

B cell chronic lymphocytic leukemia (CLL) is a clinically heterogeneous disease characterized by accumulation of malignant CD5+ B cells. Multiple molecular events likely contribute to malignant transformation; no single genetic abnormality or event has been shown to be responsible for development of the disease. Significant advances have recently been made towards understanding the genetic and molecular basis for the etiology and clinical course of CLL. Our current understanding is only now bringing us to the point where we can use this information in management and in developing new therapies for patients with CLL. Familial clustering of CLL cases is not uncommon and implicates a genetic basis for the development of the disease in some individuals. Potential interventions in this instance could employ strategies of gene transfer or gene therapy to correct genetic defects or strategies of chemoprevention, none of which is currently under investigation. Greater potential for therapeutic intervention rests with targeting molecular aberrations and altered gene expression in leukemia cells, for example, over expression of the anti-apoptotic proteins of the Bcl-2 family. CLL follows a variable clinical course, with some patients not needing treatment for many years and responding to therapy completely and repeatedly. Other patients have rapidly progressive disease that is refractory to currently available agents and they quickly succumb to their disease. One major recent advance has been the identification of molecular and genetic prognostic factors that can be used in early-stage patients to identify those likely to rapidly progress. This affords the opportunity to tailor management for patients based on the predictable aggressiveness of their disease. Molecular and genetic findings are increasingly influencing management decisions in CLL. Bone marrow transplantation may be considered for a patient with unfavorable prognostic features earlier than for a patient with favorable features and same clinical stage of disease. It is likely that these genetic and molecular-based factors will be targets of new treatment modalities that fundamentally change the management of this disease. In this review we detail the current understanding of the genetics and molecular biology of CLL and introduce potentials for therapeutic intervention.


Subject(s)
Leukemia, Lymphocytic, Chronic, B-Cell/genetics , Biomarkers, Tumor/analysis , Chromosome Aberrations , Combined Modality Therapy , Epigenesis, Genetic , Genetic Therapy , Humans , Immunoglobulin Heavy Chains/genetics , Leukemia, Lymphocytic, Chronic, B-Cell/therapy , MicroRNAs , Models, Biological , Mutation
20.
Am J Clin Pathol ; 123(4): 594-602, 2005 Apr.
Article in English | MEDLINE | ID: mdl-15743747

ABSTRACT

We studied the clinicopathologic, immunophenotypic, and cytogenetic features of 26 patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) associated with serum IgM paraprotein. The study group (16 men; 10 women; median age, 64 years; range, 40-82 years) represents approximately 2.5% of CLL/SLL cases at our institution. The paraprotein level ranged from 1 to 14 g/L (median, 4 g/L). Neoplasms in bone marrow were composed of small round lymphocytes arranged in nodular (n = 6), diffuse (n = 5), interstitial (n = 5), or mixed (n = 10) patterns. All cases were positive for monotypic surface immunoglobulin light chain, IgM/IgD, CD5, CD19, CD20, and CD23. CD11c (14/20 [70%]), CD79b (11/19 [58%]), FMC-7 (11/26 [42%]), CD22 (8/20 [40%]), and ZAP-70 (6/19 [32%]) were expressed in subsets of cases. Of 17 bone marrow specimens assessed by conventional cytogenetics, 6 were abnormal and 11 were diploid. The overall survival of this group (median follow-up, 24 months) was not significantly different from that for an age-, sex-and stage-matched group of 52 CLL/SLL patients without IgM paraprotein (P = .60). We conclude that CLL/SLL cases with serum IgM paraprotein are similar to other CLL/SLL cases in their clinicopathologic and immunophenotypic features.


Subject(s)
Immunoglobulin M/immunology , Leukemia, Lymphocytic, Chronic, B-Cell/immunology , Paraproteins/immunology , Adult , Aged , Aged, 80 and over , Blood Protein Electrophoresis , Bone Marrow/pathology , Chromosome Aberrations , Female , Flow Cytometry , Humans , Immunoglobulin M/blood , Immunohistochemistry , Immunophenotyping , Leukemia, Lymphocytic, Chronic, B-Cell/genetics , Leukemia, Lymphocytic, Chronic, B-Cell/pathology , Male , Middle Aged , Protein-Tyrosine Kinases/metabolism , ZAP-70 Protein-Tyrosine Kinase
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