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Oncology (Williston Park, N.Y.) Aug 2015Previously obscured within other designations of aggressive lymphomas, peripheral T-cell lymphoma (PTCL) now represents 23 different subtypes of non-Hodgkin lymphoma... (Review)
Review
Previously obscured within other designations of aggressive lymphomas, peripheral T-cell lymphoma (PTCL) now represents 23 different subtypes of non-Hodgkin lymphoma (NHL). Despite the many subtypes now recognized, PTCL represents only approximately 10% of all NHL cases diagnosed. Positron emission tomography/computed tomography has become essential to accurate staging and response-evaluation for PTCL. In comparison to aggressive B-cell NHL, patients with PTCL will more often be refractory to initial therapy, and chemosensitive patients will have shorter disease-free periods. Anthracycline-based regimens, often with the inclusion of etoposide, are commonly used during induction therapy. Consolidation with high-dose therapy and autologous stem cell transplantation (ASCT) in first chemosensitive remission appears to provide the best outcome in common nodal PTCL subtypes. The commonly defined nodal subtypes are PTCL not otherwise specified, angioimmunoblastic T-cell lymphoma, and anaplastic lymphoma kinase (ALK)-positive or ALK-negative anaplastic large-cell lymphoma (ALCL). Four agents have been approved by the US Food and Drug Administration for use in the relapsed/refractory (rel/ref) setting, including belinostat (2014), romidepsin (2011), brentuximab vedotin (2011), and pralatrexate (2009). Brentuximab vedotin was approved only for the ALCL subtype. These agents continue to be studied as combinations in the rel/ref setting and as additions or substitutions for other agents in upfront multiagent chemotherapy regimens. Patients who have responded to treatment in the rel/ref setting and are considered transplant-eligible should be considered for allogeneic stem cell transplantation, especially those with previous ASCT. Upfront allogeneic stem cell transplantation remains a research question in the majority of PTCL subtypes, but data are emerging.
Topics: Hematopoietic Stem Cell Transplantation; Humans; Lymphoma, T-Cell, Peripheral; Transplantation, Homologous
PubMed: 26281838
DOI: No ID Found -
Clinical Cancer Research : An Official... Oct 2020Romidepsin dosing recommendations for patients with malignancy and varying degrees of hepatic dysfunction was lacking at the time of regulatory approval for T-cell...
PURPOSE
Romidepsin dosing recommendations for patients with malignancy and varying degrees of hepatic dysfunction was lacking at the time of regulatory approval for T-cell lymphoma. We conducted a multicenter phase I clinical trial (ETCTN-9008) via the NCI Organ Dysfunction Working Group to investigate safety, first cycle MTD, and pharmacokinetic profile of romidepsin in this setting.
PATIENTS AND METHODS
Patients with select advanced solid tumors or hematologic malignancies were stratified according to hepatic function. Romidepsin was administered intravenously on days 1, 8, and 15 of a 28-day cycle and escalation followed a 3 + 3 design in moderate and severe impairment cohorts. Blood samples for detailed pharmacokinetic analyses were collected after the first dose.
RESULTS
Thirty-one patients received one dose of romidepsin and were evaluable for pharmacokinetic analyses in normal ( = 12), mild ( = 8), moderate ( = 5), and severe ( = 6) cohorts. Adverse events across cohorts were similar, and dose-limiting toxicity occurred in two patients (mild and severe impairment cohorts). The MTD was not determined because the geometric mean AUC values of romidepsin in moderate (7 mg/m) and severe (5 mg/m) impairment cohort were 114% and 116% of the normal cohort (14 mg/m).
CONCLUSIONS
Data from the ETCTN-9008 trial led to changes in the romidepsin labeling to reflect starting dose adjustment for patients with cancer and moderate and severe hepatic impairment, with no adjustment for mild hepatic impairment.
Topics: Adult; Aged; Antineoplastic Agents; Depsipeptides; Female; Humans; Liver; Liver Diseases; Lymphoma, T-Cell; Male; Middle Aged; Multiple Organ Failure; National Cancer Institute (U.S.); United States
PubMed: 32816943
DOI: 10.1158/1078-0432.CCR-20-1412 -
Blood Apr 2024Patients with Sézary syndrome (SS), a leukemic variant of cutaneous T-cell lymphoma (CTCL), are prone to Staphylococcus aureus infections and have a poor prognosis due...
Patients with Sézary syndrome (SS), a leukemic variant of cutaneous T-cell lymphoma (CTCL), are prone to Staphylococcus aureus infections and have a poor prognosis due to treatment resistance. Here, we report that S aureus and staphylococcal enterotoxins (SE) induce drug resistance in malignant T cells against therapeutics commonly used in CTCL. Supernatant from patient-derived, SE-producing S aureus and recombinant SE significantly inhibit cell death induced by histone deacetylase (HDAC) inhibitor romidepsin in primary malignant T cells from patients with SS. Bacterial killing by engineered, bacteriophage-derived, S aureus-specific endolysin (XZ.700) abrogates the effect of S aureus supernatant. Similarly, mutations in major histocompatibility complex (MHC) class II binding sites of SE type A (SEA) and anti-SEA antibody block induction of resistance. Importantly, SE also triggers resistance to other HDAC inhibitors (vorinostat and resminostat) and chemotherapeutic drugs (doxorubicin and etoposide). Multimodal single-cell sequencing indicates T-cell receptor (TCR), NF-κB, and JAK/STAT signaling pathways (previously associated with drug resistance) as putative mediators of SE-induced drug resistance. In support, inhibition of TCR-signaling and Protein kinase C (upstream of NF-κB) counteracts SE-induced rescue from drug-induced cell death. Inversely, SE cannot rescue from cell death induced by the proteasome/NF-κB inhibitor bortezomib. Inhibition of JAK/STAT only blocks rescue in patients whose malignant T-cell survival is dependent on SE-induced cytokines, suggesting 2 distinct ways SE can induce drug resistance. In conclusion, we show that S aureus enterotoxins induce drug resistance in primary malignant T cells. These findings suggest that S aureus enterotoxins cause clinical treatment resistance in patients with SS, and antibacterial measures may improve the outcome of cancer-directed therapy in patients harboring S aureus.
Topics: Humans; Sezary Syndrome; Staphylococcus aureus; NF-kappa B; T-Lymphocytes; Enterotoxins; Lymphoma, T-Cell, Cutaneous; Receptors, Antigen, T-Cell; Staphylococcal Infections; Histone Deacetylase Inhibitors; Skin Neoplasms; Drug Resistance
PubMed: 38170178
DOI: 10.1182/blood.2023021671 -
EBioMedicine Sep 2023Biomarkers predicting the outcome of HIV-1 virus control in natural infection and after therapeutic interventions in HIV-1 cure trials remain poorly defined. The BCN02...
BACKGROUND
Biomarkers predicting the outcome of HIV-1 virus control in natural infection and after therapeutic interventions in HIV-1 cure trials remain poorly defined. The BCN02 trial (NCT02616874), combined a T-cell vaccine with romidepsin (RMD), a cancer-drug that was used to promote HIV-1 latency reversal and which has also been shown to have beneficial effects on neurofunction. We conducted longitudinal plasma proteomics analyses in trial participants to define biomarkers associated with virus control during monitored antiretroviral pause (MAP) and to identify novel therapeutic targets that can improve future cure strategies.
METHODS
BCN02 was a phase I, open-label, single-arm clinical trial in early-treated, HIV infected individuals. Longitudinal plasma proteomes were analyzed in 11 BCN02 participants, including 8 participants that showed a rapid HIV-1 plasma rebound during a monitored antiretroviral pause (MAP-NC, 'non-controllers') and 3 that remained off ART with sustained plasma viremia <2000 copies/ml (MAP-C, 'controllers'). Inflammatory and neurological proteomes in plasma were evaluated and integration data analysis (viral and neurocognitive parameters) was performed. Validation studies were conducted in a cohort of untreated HIV-1+ individuals (n = 96) and in vitro viral replication assays using an anti-CD33 antibody were used for functional validation.
FINDINGS
Inflammatory plasma proteomes in BCN02 participants showed marked longitudinal alterations. Strong proteome differences were also observed between MAP-C and MAP-NC, including in baseline timepoints. CD33/Siglec-3 was the unique plasma marker with the ability to discriminate between MAPC-C and MAP-NC at all study timepoints and showed positive correlations with viral parameters. Analyses in an untreated cohort of PLWH confirmed the positive correlation between viral parameters and CD33 plasma levels, as well as PBMC gene expression. Finally, adding an anti-CD33 antibody to in vitro virus cultures significantly reduced HIV-1 replication and proviral levels in T cells and macrophages.
INTERPRETATION
This study indicates that CD33/Siglec-3 may serve as a predictor of HIV-1 control and as potential therapeutic tool to improve future cure strategies.
FUNDING
Spanish Science and Innovation Ministry (SAF2017-89726-R and PID2020-119710RB-I00), NIH (P01-AI131568), European Commission (GA101057548) and a Grifols research agreement.
Topics: Humans; CD4-Positive T-Lymphocytes; HIV Infections; HIV Seropositivity; HIV-1; Leukocytes, Mononuclear; Proteome; Proteomics; Sialic Acid Binding Ig-like Lectin 3; Vaccination; Viral Load; Anti-HIV Agents; Biomarkers
PubMed: 37506557
DOI: 10.1016/j.ebiom.2023.104732 -
Biomedicine & Pharmacotherapy =... Sep 2021Brain insulin signal anomalies are implicated in Alzheimer's disease (AD) pathology. In this background, metformin, an insulin sensitizer's neuroprotective...
Brain insulin signal anomalies are implicated in Alzheimer's disease (AD) pathology. In this background, metformin, an insulin sensitizer's neuroprotective effectiveness, has been established in the prior findings. In the present investigation, combining an epigenetic modulator, romidepsin, and metformin will improve the gene expressions of neurotrophic factors and reduce AD-associated biochemical and cellular changes by loading them mainly into a nanocarrier surface-modified framework for improved therapeutic effectiveness and bioavailability. In the present investigation, the mediated intra-cerebroventricular streptozocin (3 mg/kg) AD of the model was loaded with metformin and romidepsin into a poloxamer stabilized polymer nanocarrier system. Free combination drug therapy (Romidepsin 25 mg/kg and metformin 5 mg/kg) reduced biochemical and cellular variations over three weeks, respectively, compared to either free treatment (Romidepsin 50 mg/kg and metformin 10 mg/kg). The nanoformulations (Romidepsin 25 mg/kg and Metformin 5 mg/kg), as shown by enhanced significantly reduce stress and high neurotrophic factors, has also exerted superior neurological effectiveness than the free combination of drugs. Eventually, through the Poloxamer stable polymeric nanocarrier framework, the synergistic neuroprotective efficacy of metformin and romidepsin has improved.
Topics: Alzheimer Disease; Animals; Antibiotics, Antineoplastic; Biological Availability; Depsipeptides; Drug Carriers; Drug Synergism; Drug Therapy, Combination; Epigenesis, Genetic; Hypoglycemic Agents; Injections, Intraventricular; Metformin; Mice; Nanostructures; Nerve Growth Factors; Poloxamer; Streptozocin
PubMed: 34323698
DOI: 10.1016/j.biopha.2021.111864 -
Critical Reviews in Oncology/hematology Mar 2016Primary cutaneous T-cell lymphomas (CTCLs), such as mycosis fungoides and Sézary syndrome, are a rare group of non-Hodgkin lymphomas, usually treated using a multimodal... (Review)
Review
Primary cutaneous T-cell lymphomas (CTCLs), such as mycosis fungoides and Sézary syndrome, are a rare group of non-Hodgkin lymphomas, usually treated using a multimodal approach. Unfortunately, many patients go on to develop relapsed/refractory disease. Systemic treatment for relapsed/refractory CTCL has historically relied on chemotherapies and interferons, and while active, responses are often short-lived. Three drugs are now approved in the US to treat relapsed/refractory CTCL including the oral retinoid, bexarotene, and histone deacetylase inhibitors, romidepsin and vorinostat. Although response rates are typically <35%, romidepsin and vorinostat can induce some durable responses in heavily pretreated patients and alleviate bothersome symptoms, such as pruritus. New studies indicate that the anti-CD30 antibody-drug conjugate brentuximab vedotin, anti-CCR4 antibody mogamulizumab, and fusion protein immunotoxin A-dmDT390-bisFv(UCHT1) may be particularly active in this setting. In this paper, we present an exhaustive review of the clinical data on current and possible future drug treatment options for relapsed/refractory CTCL.
Topics: Antineoplastic Combined Chemotherapy Protocols; Drug Resistance, Neoplasm; Humans; Lymphoma, T-Cell, Cutaneous; Neoplasm Recurrence, Local; Salvage Therapy; Skin Neoplasms
PubMed: 26811014
DOI: 10.1016/j.critrevonc.2015.12.018 -
JAAD Case Reports May 2016
PubMed: 27486589
DOI: 10.1016/j.jdcr.2016.05.013 -
Frontiers in Cell and Developmental... 2021New patterns of gene expression are enacted and regulated during tissue regeneration. Histone deacetylases (HDACs) regulate gene expression by removing acetylated lysine...
New patterns of gene expression are enacted and regulated during tissue regeneration. Histone deacetylases (HDACs) regulate gene expression by removing acetylated lysine residues from histones and proteins that function directly or indirectly in transcriptional regulation. Previously we showed that romidepsin, an FDA-approved HDAC inhibitor, potently blocks axolotl embryo tail regeneration by altering initial transcriptional responses to injury. Here, we report on the concentration-dependent effect of romidepsin on transcription and regeneration outcome, introducing an experimental and conceptual framework for investigating small molecule mechanisms of action. A range of romidepsin concentrations (0-10 μM) were administered from 0 to 6 or 0 to 12 h post amputation (HPA) and distal tail tip tissue was collected for gene expression analysis. Above a threshold concentration, romidepsin potently inhibited regeneration. Sigmoidal and biphasic transcription response curve modeling identified genes with inflection points aligning to the threshold concentration defining regenerative failure verses success. Regeneration inhibitory concentrations of romidepsin increased and decreased the expression of key genes. Genes that associate with oxidative stress, negative regulation of cell signaling, negative regulation of cell cycle progression, and cellular differentiation were increased, while genes that are typically up-regulated during appendage regeneration were decreased, including genes expressed by fibroblast-like progenitor cells. Using single-nuclei RNA-Seq at 6 HPA, we found that key genes were altered by romidepin in the same direction across multiple cell types. Our results implicate HDAC activity as a transcriptional mechanism that operates across cell types to regulate the alternative expression of genes that associate with regenerative success versus failure outcomes.
PubMed: 35036404
DOI: 10.3389/fcell.2021.767377 -
International Journal of Medical... 2019T-cell lymphomas are a heterogeneous group of cancers with different pathogenesis and poor prognosis. Histone deacetylases (HDACs) are epigenetic modifiers that modulate... (Review)
Review
T-cell lymphomas are a heterogeneous group of cancers with different pathogenesis and poor prognosis. Histone deacetylases (HDACs) are epigenetic modifiers that modulate many key biological processes. In recent years, HDACs have been fully investigated for their roles and potential as drug targets in T-cell lymphomas. In this review, we have deciphered the modes of action of HDACs, HDAC inhibitors as single agents, and HDACs guided combination therapies in T-cell lymphomas. The overview of HDACs on the stage of T-cell lymphomas, and HDACs guided therapies both as single agents and combination regimens endow great opportunities for the cure of T-cell lymphomas.
Topics: Antineoplastic Combined Chemotherapy Protocols; Autophagy; Cytokines; Depsipeptides; Epigenesis, Genetic; Gene Expression Regulation, Enzymologic; Gene Expression Regulation, Neoplastic; Histone Deacetylase Inhibitors; Histone Deacetylases; Humans; Hydroxamic Acids; Lymphoma, T-Cell; Molecular Targeted Therapy; Sulfonamides; Vorinostat
PubMed: 30911277
DOI: 10.7150/ijms.30154 -
American Journal of Hematology Oct 2021Romidepsin (histone deacetylase inhibitor), lenalidomide (immunomodulatory agent), and carfilzomib (proteasome inhibitor), have efficacy and lack cumulative toxicity in...
Romidepsin (histone deacetylase inhibitor), lenalidomide (immunomodulatory agent), and carfilzomib (proteasome inhibitor), have efficacy and lack cumulative toxicity in relapsed/refractory lymphoma. We performed two investigator initiated sequential phase I studies to evaluate the maximum tolerated dose (MTD) of romidepsin and lenalidomide (regimen A) and romidepsin, lenalidomide, and carfilzomib (regimen B) in relapsed/refractory lymphoma. Cohorts in T-cell lymphoma (TCL), B-cell lymphoma (BCL) were enrolled at the MTD. Forty-nine patients were treated in study A (27 TCL, 17 BCL, 5 Hodgkin lymphoma (HL)) and 27 (16 TCL, 11 BCL) in study B. The MTD of regimen A was romidepsin 14 mg/m IV on days 1, 8, and 15 and lenalidomide 25 mg oral on days 1-21 of a 28-day cycle. The MTD of regimen B was romidepsin 8 mg/m on days 1 and 8, lenalidomide 10 mg oral on days 1-14 and carfilzomib 36 mg/m IV on days 1 and 8 of a 21-day cycle. In study A, 94% had AEs ≥Grade 3, most commonly neutropenia (49%), thrombocytopenia (53%), and electrolyte abnormalities (49%). In study B 59% had AEs ≥Grade 3, including thrombocytopenia (30%) and neutropenia (26%). In study A the ORR was 49% (50% TCL, 47% BCL, 50% HL). In study B the ORR was 48% (50% TCL, 50% BCL). For study A and B the median progression free survival (PFS) was 5.7 months and 3.4 months respectively with 11 patients proceeding to allogeneic transplant. The combinations of romidepsin and lenalidomide and of romidepsin, lenalidomide and carfilzomib showed activity in relapsed/refractory lymphoma with an acceptable safety profile.
Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Depsipeptides; Female; Humans; Lenalidomide; Lymphoma; Male; Maximum Tolerated Dose; Middle Aged; Neoplasm Recurrence, Local; Oligopeptides; Treatment Outcome
PubMed: 34251048
DOI: 10.1002/ajh.26288