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Case Report: No Response to Liposomal Daunorubicin in a Patient with Drug-Resistant HIV-Associated Visceral Leishmaniasis  [PDF]
Nicholas J. Gow?,Robert N. Davidson?,Rob Ticehurst?,Andrew Burns?,Mark G. Thomas
PLOS Neglected Tropical Diseases , 2015, DOI: 10.1371/journal.pntd.0003983
Abstract: Visceral leishmaniasis (VL) in patients with HIV co-infection presents a significant therapeutic challenge due to the lessened chance of achieving long-term cure. We report a case of VL in a 60-year-old man with HIV infection who became refractory to anti-leishmania treatment due to multi-drug resistance. In the face of a worsening clinical situation, and with no other options available, he was treated with an experimental regimen of liposomal daunorubicin, which has previously been shown to have in vitro activity against Leishmania donovani and to be effective treatment of VL in animal studies. To our knowledge, he was the first patient with VL and HIV co-infection to have this treatment evaluated. We report on the lack of response to this treatment and possible causes for its failure.
Role of combination bortezomib and pegylated liposomal doxorubicin in the management of relapsed and/or refractory multiple myeloma
Jatin J Shah, Robert Z Orlowski, Sheeba K Thomas
Therapeutics and Clinical Risk Management , 2009, DOI: http://dx.doi.org/10.2147/TCRM.S3340
Abstract: le of combination bortezomib and pegylated liposomal doxorubicin in the management of relapsed and/or refractory multiple myeloma Review (4449) Total Article Views Authors: Jatin J Shah, Robert Z Orlowski, Sheeba K Thomas Published Date January 2009 Volume 2009:5 Pages 151 - 159 DOI: http://dx.doi.org/10.2147/TCRM.S3340 Jatin J Shah1, Robert Z Orlowski1,2, Sheeba K Thomas1 1Departments of Lymphoma/Myeloma; 2Experimental Therapeutics, Division of Cancer Medicine, University of Texas MD Anderson Cancer Center, Houston, Texas, USA Abstract: The first in class proteasome inhibitor bortezomib (B) received its initial regulatory approval for therapy of patients with multiple myeloma (MM) in the relapsed/refractory setting. Modulation of proteasome function, however, is also a rational strategy for chemosensitization, and a variety of agents have shown synergistic activity with bortezomib pre-clinically, including anthracyclines. This formed the basis for evaluation of a regimen of bortezomib with pegylated liposomal doxorubicin (PLD). PLD+B, in a phase I study, induced a predictable and manageable toxicity profi le, and showed encouraging anti-MM activity. In a recent international, randomized phase III trial, PLD+B demonstrated a superior overall response rate and response quality compared to bortezomib alone, as well as a longer time to progression, duration of response, progression-free survival, and overall survival. Sub-analyses revealed benefits in almost all clinically relevant subgroups, including several which would be considered to have high-risk disease. These findings have led to the establishment of the PLD+B regimen as one of the standards of care for patients with relapsed and/or refractory myeloma. Efforts are now underway to build on this combination further by adding other active anti-myeloma agents. In this review, we will discuss the role of PLD+B as an important addition to our therapeutic armamentarium for patients with MM.
Role of combination bortezomib and pegylated liposomal doxorubicin in the management of relapsed and/or refractory multiple myeloma
Jatin J Shah,Robert Z Orlowski,Sheeba K Thomas
Therapeutics and Clinical Risk Management , 2009,
Abstract: Jatin J Shah1, Robert Z Orlowski1,2, Sheeba K Thomas11Departments of Lymphoma/Myeloma; 2Experimental Therapeutics, Division of Cancer Medicine, University of Texas MD Anderson Cancer Center, Houston, Texas, USAAbstract: The first in class proteasome inhibitor bortezomib (B) received its initial regulatory approval for therapy of patients with multiple myeloma (MM) in the relapsed/refractory setting. Modulation of proteasome function, however, is also a rational strategy for chemosensitization, and a variety of agents have shown synergistic activity with bortezomib pre-clinically, including anthracyclines. This formed the basis for evaluation of a regimen of bortezomib with pegylated liposomal doxorubicin (PLD). PLD+B, in a phase I study, induced a predictable and manageable toxicity profi le, and showed encouraging anti-MM activity. In a recent international, randomized phase III trial, PLD+B demonstrated a superior overall response rate and response quality compared to bortezomib alone, as well as a longer time to progression, duration of response, progression-free survival, and overall survival. Sub-analyses revealed benefits in almost all clinically relevant subgroups, including several which would be considered to have high-risk disease. These findings have led to the establishment of the PLD+B regimen as one of the standards of care for patients with relapsed and/or refractory myeloma. Efforts are now underway to build on this combination further by adding other active anti-myeloma agents. In this review, we will discuss the role of PLD+B as an important addition to our therapeutic armamentarium for patients with MM.Keywords: multiple myeloma, relapsed/refractory, pegylated liposomal doxorubicin, bortezomib, Doxil , Velcade
Tumor lysis syndrome presenting in a patient with multiple myeloma treated with vincristine, adriamycin, and dexamethasone: a case report  [PDF]
Hiroto Kaneko,Yumina Sugahara,Muneo Ohshiro,Yasuhiko Tsutsumi
Open Journal of Hematology , 2012,
Abstract: Multiple myeloma has seldom been reported to complicate tumor lysis syndrome since it is an indolent disease. We report a case with multiple myeloma who rapidly developed tumor lysis syndrome after conventional induction therapy.A 63-year-old Japanese woman presented with dyspnea on effort was diagnosed as IgA-lambda type myeloma. According to the International Staging System, her stage was defined as III because of elevated serum beta-2 microglobulin at 72mg/L. Remission induction consisted of continuous intravenous administration of vincristine of 0.4mg/day and adriamycin of 15mg/day through days 1 to 4 and infusion of dexamethasone of 40mg/day on days 1-4 was given. On day 7, she felt general fatigue and loss of appetite and her serum uric acid, creatinine, and potassium elevated to 898.1μmol/L, 9.8mg/dL, and 6.7mmol/L, respectively. Inversely, serum calcium decreased to 2.0mmol/L. Under the diagnosis of tumor lysis syndrome, she was treated with hydration and diuretics, resulted in immediate regression of her symptoms and recovery of laboratory data.Besides conventional chemotherapy, newly introduced agents have also been reported to cause tumor lysis in myeloma. While previous description has identified renal dysfunction to play a crucial role in the development of tumor lysis syndrome, myeloma often complicates impaired renal function. Since International Staging System is widely applied for myeloma patients, beta-2 microglobulin that represents renal function is thought to be examined in most of them. Taken together, elevated beta-2 microglobulin appears to easily predict a risk for tumor lysis syndrome. Thus, we postulate that prevention for excessive tumor lysis should be considered for myeloma patients with elevated beta-2 microglobulin.
Response to dexamethasone is glucose-sensitive in multiple myeloma cell lines
Ellen Friday, Johnathan Ledet, Francesco Turturro
Journal of Experimental & Clinical Cancer Research , 2011, DOI: 10.1186/1756-9966-30-81
Abstract: Multiple myeloma (MM) cells were grown in 5 or 20 mM/L glucose with or without 25 μM DEX. Semiquantitative reverse transcription-PCR (RT-PCR) was used to assess TXNIP RNA expression in response to glucose and DEX. ROS were detected by 5-6-chloromethyl-2',7'-dichlorodihydrofluorescein diacetate (CM-H2DCFDA). TRX activity was assayed by the insulin disulfide-reducing assay. Proliferation was evaluated using CellTiter96 reagent with 490-nm absorbtion and used to calculate the DEX IC50 in 20 mM/L glucose using the Chou's dose effect equation.TXNIP RNA level responded to glucose or DEX with the same order of magnitude ARH77 > NCIH929 > U266B1 in these cells. MC/CAR cells were resistant to the regulation. ROS level increased concurrently with reduced TRX activity. Surprisingly glucose increased TRX activity in MC/CAR cells keeping ROS level low. DEX and glucose were lacking the expected additive effect on TXNIP RNA regulation when used concurrently in sensitive cells. ROS level was significantly lower when DEX was used in conditions of hyperglycemia in ARH77/NCIH9292 cells but not in U266B1 cells. Dex-IC50 increased 10-fold when the dose response effect of DEX was evaluated with glucose in ARH && and MC/Car cellsOur study shows for the first time that glucose or DEX regulates important components of ROS production through TXNIP modulation or direct interference with TRX activity in MM cells. We show that glucose modulates the activity of DEX through ROS regualtion in MM cells. A better understanding of these pathways may help in improving the efficacy and reducing the toxicity of DEX, a drug still highly used in the treatment of MM. Our study also set the ground to study the relevance of the metabolic milieu in affecting drug response and toxicity in diabetic versus non-diabetic patients with MM.Despite the booming of novel agents for the treatment of multiple myeloma (MM) such as proteasome inhibitor bortezomib, and immuno-modulator agents thalidomide or lenalidomide, de
Updated survivals and prognostic factor analysis in myeloma treated by a staged approach use of bortezomib/thalidomide/dexamethasone in transplant eligible patients
Chor Chim
Journal of Translational Medicine , 2010, DOI: 10.1186/1479-5876-8-124
Abstract: Herein, with an additional 13 months of follow-up, we reported the updated survivals, and examined potential prognostic factors impacting event-free (EFS) and overall survival (OS).With a median follow-up of 30 months, the projected OS was 73% and EFS was 50.2%. Age, gender, clinical stage and DAPK methylation could not account for the differential chemosensitivity. Advanced ISS stage and DAPK methylation adversely impacted OS whereas oligoclonal reconstitution predicted superior EFS.Our staged approach illustrated an economical use of expensive targeted agents while preserving a good CR rate and OS. The comparable survivals of chemosensitive and less chemosensitive patients suggested the staged approach might have abolished the adverse prognostic impact of suboptimal chemosensitivity. Finally, the adverse impact of DAPK methylation and favorable impact of oligoclonal reconstitution in myeloma warrants further study.Bortezomib, an NFkB inhibitor, is an active agent for the treatment of myeloma (MM). After the demonstration of its efficacy as salvage therapy in chemo-resistant or refractory myeloma patients with a CR rate of 9% [1,2]. a high CR rate has also been demonstrated when bortezomib was used in induction therapy in newly diagnosed myeloma patients. For instance, a CR rate of 43% and 30% was observed when bortezomib-based induction therapy was applied in both transplant-eligible and transplant-ineligible myeloma patients [3,4].In Hong Kong, we have adopted a staged approach, in which newly diagnosed, transplant-eligible myeloma patients were risk-stratified according to their initial chemosensitivity, wherein VAD-chemosensitive patients underwent autologous hematopoietic stem cell transplantation (auto-HSCT) while less VAD-chemosensitive patients received salvage therapy of bortezomib/thalidomide/dexamethasone (VTD) before auto-HSCT.5 (Figure 1) We have reported frequent occurrence of oligoclonal reconstitution, frequent central nervous system myeloma (one wi
Liposomal encapsulation enhances and prolongs the anti-inflammatory effects of water-soluble dexamethasone phosphate in experimental adjuvant arthritis
Rebecca Anderson, Angels Franch, Margarida Castell, Francisco J Perez-Cano, Rolf Br?uer, Dirk Pohlers, Mieczyslaw Gajda, Alexandros P Siskos, Theodora Katsila, Constantin Tamvakopoulos, Una Rauchhaus, Steffen Panzner, Raimund W Kinne
Arthritis Research & Therapy , 2010, DOI: 10.1186/ar3089
Abstract: Efficacy was assessed clinically and histologically using standard scores. Non-specific and specific immune parameters were monitored. Activation of peritoneal macrophages was analyzed via cytokine profiling. Pharmacokinetics/biodistribution of DxM in plasma, synovial membrane, spleen and liver were assessed via mass spectrometry.Liposomal DxM-P (3 × 1 mg/kg body weight; administered intravenously (i.v.) on Days 14, 15 and 16 of AA) suppressed established AA, including histological signs, erythrocyte sedimentation rate, white blood cell count, circulating anti-mycobacterial IgG, and production of interleukin-1beta (IL-1β) and IL-6 by peritoneal macrophages. The suppression was strong and long-lasting. The clinical effects of liposomal DxM-P were dose-dependent for dosages between 0.01 and 1.0 mg/kg. Single administration of 1 mg/kg liposomal DxM-P and 3 × 1 mg/kg of free DxM-P showed comparable effects consisting of a partial and transient suppression. Moreover, the effects of medium-dose liposomal DxM-P (3 × 0.1 mg/kg) were equal (in the short term) or superior (in the long term) to those of high-dose free DxM-P (3 × 1 mg/kg), suggesting a potential dose reduction by a factor between 3 and 10 by liposomal encapsulation. For at least 48 hours after the last injection, the liposomal drug achieved significantly higher levels in plasma, synovial membrane, spleen and liver than the free drug.This new PEG-free formulation of macrophage-targeting liposomal DxM-P considerably reduces the dose and/or frequency required to treat AA, with a potential to enhance or prolong therapeutic efficacy and limit side-effects also in the therapy of rheumatoid arthritis. Depot and/or recirculation effects in plasma, inflamed joint, liver, and spleen may contribute to this superiority of liposomally encapsulated DxM-P.Rheumatoid arthritis (RA) is a systemic disorder of unknown etiology characterized by chronic inflammation and symmetric, progressive destruction of arthritic joints. The ab
Separating therapeutic efficacy from glucocorticoid side-effects in rodent arthritis using novel, liposomal delivery of dexamethasone phosphate: long-term suppression of arthritis facilitates interval treatment
Una Rauchhaus, Franz Schwaiger, Steffen Panzner
Arthritis Research & Therapy , 2009, DOI: 10.1186/ar2889
Abstract: Therapeutic efficacy and persistence of free and liposomal dexamethasone phosphate (DXM-P) were determined in mouse collagen-induced arthritis. For regimens with equal therapeutic benefit, the side-effect profiles were analysed over time with respect to collagen breakdown, suppression of the hypothalamus-pituitary-adrenal (HPA) axis, changes in blood glucose levels and the haematological profile. In addition, the presence of drug was monitored in plasma.Liposomal DXM-P, but not free drug, resulted in a persistent anti-inflammatory effect. Comparable clinical benefit was achieved with a single administration of 4 mg/kg liposomal DXM-P or daily administrations of 1.6 mg/kg free drug for at least 7 days. For the liposomal form, but not for the free form, we observed a limitation of the suppression of the HPA axis in time and an absence of the drug-induced gluconeogenesis.Liposomal DXM-P, but not free DXM-P, achieves therapeutic persistence in mouse collagen-induced arthritis, which results in drug-free periods of therapeutic benefit. The physical absence of drug after day 2 is associated with a reduction of the typical glucocorticoid side-effects profile. Liposomal DXM-P thereby has an improved therapeutic window.Glucocorticoids have long been used in the treatment of rheumatoid arthritis, and are an essential part of the first-line anti-inflammatory treatment. Dose escalation and long-term, chronic use of glucocorticoids lead to a number of well-characterized clinical side-effects, however, such as Cushing syndrome [1,2], diabetes [3], or bone demineralization [4], all of which are limiting their therapeutic use.Strategies for an improvement of the therapeutic index of glucocorticoids focus on the drug molecule itself, its specificity or metabolic conversion [5,6]. Others have investigated selective glucocorticoid receptor agonists to improve the ratio between the therapeutic effect and adverse reaction [7,8]. In addition, the targeted delivery of these drugs using li
Front line treatment of elderly multiple myeloma in the era of novel agents  [cached]
Marie-Dominique Venon,Aldo M Roccaro,Julie Gay,Anne-Sophie Moreau
Biologics: Targets and Therapy , 2008,
Abstract: Marie-Dominique Venon2, Aldo M Roccaro1,3, Julie Gay2, Anne-Sophie Moreau1,2, Remy Dulery2, Thierry Facon2, Irene M Ghobrial1, Xavier Leleu1,21Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA; 2Service des Maladies du Sang, Hopital Huriez, CHRU, Lille, France; 3Units of Blood Diseases and Cell Therapies, University of Bresica, Medical School, Bresica, ItalyAbstract: Melphalan combined with prednisone (MP) has long been the historical treatment of reference for a large proportion of elderly myeloma (MM) patients ineligible for autologous stem cell transplantation, and is still the backbone of new regimens that include the new era of novel agents. Melphalan–prednisone–thalidomide (MPT) and melphalan–prednisone–bortezomib (Velcade , MPV), proved superior to MP, currently appear to be the treatments of choice for this population. In the near future melphalan–prednisone–lenalidomide (Revlimid , MPR) will also provide a third therapeutic option (MPT, MPV, and MPR), in elderly multiple myeloma, eventually. These options could lead to more personalized treatment approaches, based on patient comorbidities, as the three novel agents have somewhat different toxicity profiles. Dexamethasone-based regimen is another option and questions regarding the relative efficacy of melphalan-based versus low-dose dexamethasone-based regimens will require randomized phase III trials. More intensive approaches with new drug combinations or with the incorporation of polyethylene glycolated (PEGylated) liposomal doxorubicin will also require additional studies. Additionally, the important issue of maintenance treatment needs to be further investigated. These new and emerging therapies offer multiple effective treatment options for MM patients and greatly enhanced treatment strategies for clinicians.Keywords: multiple myeloma, elderly, bortezomib, thalidomide, revlimid, IMiDs, supportive care
Leptomeningeal myelomatosis in previously treated high-risk kappa light chain multiple myeloma: case report and literature review  [cached]
Ohanian M,Alaly J,Samuel S,Cable C
Blood and Lymphatic Cancer: Targets and Therapy , 2011,
Abstract: Maro Ohanian1, James Alaly2, Stephen Samuel3, Christian Cable1, Kathleen Halka11Department of Hematology/Oncology, 2Department of Radiology, 3Department of Hematopathology, Scott and White Healthcare, The Texas A&M Health Science Center College of Medicine, Temple, Texas, USAObjective: To describe leptomeningeal myelomatosis (LM) in previously treated high-risk kappa light chain multiple myeloma (MM) and to review the literature.Case report: A 71-year-old female with previously treated kappa light chain myeloma presented with right lumbosacral discomfort. Magnetic resonance imaging (MRI) of spine revealed multiple intradural masses involving the cauda equina, with mass effect on adjacent nerve roots. Brain MRI was unremarkable. Cerebrospinal fluid flow cytometry confirmed an abnormal population of plasma cells with kappa restriction; CD38, CD138, and CD56 were positive. She was originally diagnosed with kappa light chain myeloma 10 months earlier while hospitalized for anemia, thrombocytopenia, renal failure, and hypercalcemia. Bone marrow revealed plasma cell myeloma approaching 100% cellularity, with 92% plasma cells, atypical plasmacytoid cells with prominent nucleoli, and significant cytogenetic abnormalities: deleted 13, c-myc rearrangements, -X, +1. Treatments consisted of seven cycles of bortezomib with weekly dexamethasone. Her last dose had been 4 months earlier. After treatment, bone marrow demonstrated a complete remission with normal cytogenetics. Her clinical course had otherwise been indolent with a good hematologic response. After diagnosis of LM, therapy included focal external beam radiation to the cauda equina, weekly bortezomib and dexamethasone, intrathecal (IT) cytarabine liposomal every 2 weeks for five doses, and monthly IT cytarabine liposomal thereafter. The cerebrospinal fluid gradually cleared on serial lumbar punctures and follow-up MRI demonstrated near complete resolution of the intradural masses. Five months after diagnosis the patient is essentially asymptomatic.Conclusion: The incidence of central nervous system (CNS) involvement in MM patients is 1%. LM is associated with cytogenetic abnormalities and plasmablastic morphology. It can occur with a seemingly low tumor burden. Novel agents such as bortezomib allow for prolonged survival in high-risk patients; however, with inadequate CNS penetration, complications such as LM may be inevitable.Keywords: leptomeningeal myelomatosis, intrathecal, complete remission
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