ABSTRACT
Psoriatic disease, encompassing both psoriasis (Pso) and psoriatic arthritis (PsA), is closely intertwined with a significantly elevated risk of developing cardiovascular diseases. This connection is further compounded by a higher prevalence of cardiometabolic comorbidities, including type 2 diabetes, obesity, insulin resistance, arterial hypertension, and dysregulated lipid profiles. These comorbidities exceed the rates seen in the general population and compound the potential for increased mortality among those living with this condition. Recognizing the heightened cardiometabolic risk inherent in psoriatic disease necessitates a fundamental shift in the treatment paradigm. It is no longer sufficient to focus solely on mitigating inflammation. Instead, there is an urgent need to address and effectively manage the metabolic parameters that have a substantial impact on cardiovascular health. Within this context, apremilast emerges as a pivotal treatment option for psoriatic disease. What sets apremilast apart is its dual-action potential, addressing not only inflammation but also the critical metabolic parameters. This comprehensive treatment approach opens up new opportunities to improve the well-being of people living with psoriatic disease. This review delves into the multifaceted aspects involved in the development of cardiovascular disease and its intricate association with psoriatic disease. We then provide an in-depth exploration of the pleiotropic effects of apremilast, highlighting its potential to simultaneously mitigate metabolic complications and inflammation in individuals affected by these conditions.
Subject(s)
Anti-Inflammatory Agents, Non-Steroidal , Cardiovascular Diseases , Psoriasis , Thalidomide , Humans , Thalidomide/analogs & derivatives , Thalidomide/therapeutic use , Cardiovascular Diseases/drug therapy , Cardiovascular Diseases/prevention & control , Psoriasis/drug therapy , Psoriasis/metabolism , Anti-Inflammatory Agents, Non-Steroidal/therapeutic use , Arthritis, Psoriatic/drug therapy , AnimalsABSTRACT
BACKGROUND AND PURPOSE: The poor delivery of drugs to infiltrating tumor cells contributes to therapeutic failure in glioblastoma. During the early phase of an anti-angiogenic treatment, a remodeling of the tumor vasculature could occur, leading to a more functional vessel network that could enhance drug delivery. However, the restructuration of blood vessels could increase the proportion of normal endothelial cells that could be a barrier for the free diffusion of drugs. The net balance, in favor or not, of a better delivery of compounds during the course of an antiangiogenic treatment remains to be established. This study explored whether cediranib and thalidomide could modulate perfusion and vessel permeability in the brain U87 tumor mouse model. METHODS: The dynamic evolution of the diffusion of agents outside the tumor core using the fluorescent dye Evans Blue in histology and Gd-DOTA using dynamic contrast-enhanced (DCE)-MRI. CD31 labelling of endothelial cells was used to measure the vascular density. RESULTS AND INTERPRETATION: Cediranib and thalidomide effectively reduced tumor size over time. The accessibility of Evans Blue outside the tumor core continuously decreased over time. The vascular density was significantly decreased after treatment while the proportion of normal vessels remained unchanged over time. In contrast to histological studies, DCE-MRI did not tackle any significant change in hemodynamic parameters, in the core or margins of the tumor, whatever the parameter used or the pharmacokinetic model used. While cediranib and thalidomide were effective in decreasing the tumor size, they were ineffective in transiently increasing the delivery of agents in the core and the margins of the tumor.
Subject(s)
Angiogenesis Inhibitors , Brain Neoplasms , Glioblastoma , Quinazolines , Thalidomide , Glioblastoma/drug therapy , Glioblastoma/pathology , Glioblastoma/blood supply , Thalidomide/pharmacology , Thalidomide/therapeutic use , Animals , Angiogenesis Inhibitors/pharmacology , Mice , Quinazolines/pharmacology , Quinazolines/pharmacokinetics , Quinazolines/therapeutic use , Humans , Brain Neoplasms/drug therapy , Brain Neoplasms/pathology , Neovascularization, Pathologic/drug therapy , Neovascularization, Pathologic/pathology , Magnetic Resonance Imaging , Xenograft Model Antitumor Assays , Capillary Permeability/drug effects , Mice, Nude , Cell Line, Tumor , IndolesABSTRACT
RATIONALE: Light chain proximal tubulopathy (LCPT) is a rare form of renal impairment associated with multiple myeloma (MM). LCPT is caused by inclusions formed of free light chains that are typically crystalline, but can also be noncrystalline structures. PATIENT CONCERNS: A 62-year-old man was hospitalized for the investigation of abnormal urine test results lasting for 1 year and kidney-function abnormalities persisting for more than 1 month. DIAGNOSES: Noncrystalline LCPT and MM. INTERVENTIONS: The patient was treated with the lenalidomide, bortezomib, and dexamethasone and pomalidomide, bortezomib, and dexamethasone chemotherapy regimens. OUTCOMES: Complete remission of MM was achieved, and the patient's renal function returned to normal. LESSONS: This case report highlights the importance of renal pathology in the diagnosis of patients with unexplained chronic kidney disease and proteinuria.
Subject(s)
Multiple Myeloma , Humans , Male , Middle Aged , Multiple Myeloma/complications , Multiple Myeloma/drug therapy , Multiple Myeloma/diagnosis , Multiple Myeloma/pathology , Immunoglobulin Light Chains/urine , Kidney Tubules, Proximal/pathology , Dexamethasone/therapeutic use , Inclusion Bodies/pathology , Thalidomide/therapeutic use , Thalidomide/analogs & derivatives , Lenalidomide/therapeutic use , Lenalidomide/administration & dosage , Bortezomib/therapeutic useABSTRACT
A 62-year-old woman with adult T-cell leukemia/lymphoma (ATL) received umbilical cord blood transplantation (CBT) in first complete remission. However, relapse of ATL was detected on day 74 post-transplantation, as evidenced by the rapid growth of lymphoma cells in peripheral blood and an increase in soluble interleukin-2 receptor (sIL2R) levels. Discontinuation of immunosuppressant therapy alone did not improve ATL findings, but treatment with lenalidomide caused lymphoma cells to disappear from the peripheral blood and sIL2R levels to return to normal. Pancytopenia was observed as a lenalidomide-associated adverse effect, but lymphocyte counts were not reduced. The patient was judged to be in complete remission based on results of Southern blot analysis and human T-cell leukemia virus 1 (HTLV-1)-infected cell analysis using flow cytometry (HAS-Flow). Flow cytometric analysis of peripheral blood and FISH analysis of X and Y chromosomes revealed that the therapeutic effect of lenalidomide was associated with an increase in the number of donor-derived peripheral natural killer cells. ATL relapse was not observed at 13 months into lenalidomide treatment. Our results suggest that lenalidomide is an effective option for the treatment of post-transplant relapsed ATL.
Subject(s)
Cord Blood Stem Cell Transplantation , Lenalidomide , Leukemia-Lymphoma, Adult T-Cell , Recurrence , Remission Induction , Humans , Lenalidomide/administration & dosage , Lenalidomide/therapeutic use , Leukemia-Lymphoma, Adult T-Cell/therapy , Leukemia-Lymphoma, Adult T-Cell/drug therapy , Female , Middle Aged , Thalidomide/analogs & derivatives , Thalidomide/therapeutic useSubject(s)
Antineoplastic Combined Chemotherapy Protocols , Lenalidomide , Lymphoma, Mantle-Cell , Neoplasm, Residual , Humans , Lymphoma, Mantle-Cell/drug therapy , Lymphoma, Mantle-Cell/therapy , Lymphoma, Mantle-Cell/pathology , Lenalidomide/therapeutic use , Lenalidomide/administration & dosage , Neoplasm, Residual/diagnosis , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Thalidomide/analogs & derivatives , Thalidomide/therapeutic use , Thalidomide/administration & dosage , Immunotherapy/methodsABSTRACT
Pemphigus foliaceus (PF) is a superficial form of pemphigus. Treatment options for PF resemble pemphigus vulgaris, including glucocorticosteroids, immunosuppressive agents and rituximab et al. These treatment approaches can effectively improve the condition but may also be accompanied by high risks of side effects. Therefore, it is crucial to find a safe and effective treatment options for patients with PF. It will not only benefit/be necessary for patients who refuse glucocorticosteroids or immunosuppressive agents treatments, but also for patients who cannot be treated with glucocorticosteroids or immunosuppressive agents. Herein, we reported a case of PF that was treated with apremilast without systemic glucocorticosteroids or immunosuppressive agents. A 54-year-old woman presented with itchy erythema and erosions on the trunk for more than 1 month. The patient applied mometasonefuroate cream without improvement for a duration of two weeks. The past history of diabetes mellitus and atrophic gastritis was reported. Physical examination revealed scattered erythematous macules and erosions on the trunk. No mucosal involvement was observed. The condition was assessed by the pemphigus disease area index and numerical rating scale, with baseline scores of 7 and 8, respectively. Histopathological examination showed acantholysis and intraepithelial blister. Direct immunofluorescence revealed the presence of IgG and Complement 3 deposition between the acanthocytes with the reticular distribution. Based on enzyme-linked immunosorbent assay results, the levels of Dsg1 and Dsg3 antibodies were 28.18 and 0.26 kU/L respectively. The diagnosis of PF was made. This patient was successfully treated with apremilast without systemic glucocorticosteroids or immunosuppressive agents. The patient has continued with apremilast 30mg once daily for maintenance and no adverse events related to apremilast such as gastrointestinal side effects were observed during the 9-month follow-up period. In conclusion, apremilast therapy without systemic glucocorticosteroids nor immunosuppressive agents might provide an effective alternative to management of mild PF without obvious side effect.
Subject(s)
Pemphigus , Thalidomide , Humans , Pemphigus/drug therapy , Female , Middle Aged , Thalidomide/analogs & derivatives , Thalidomide/therapeutic use , Immunosuppressive Agents/therapeutic use , Treatment Outcome , Glucocorticoids/therapeutic use , Anti-Inflammatory Agents, Non-Steroidal/therapeutic useABSTRACT
OtezlaTM was first approved on March 21, 2014 for the treatment of psoriatic arthritis, on September 23, 2014 for moderate to severe plaque psoriasis and on July 19, 2019 for the treatment of oral ulcers associated with Behcet's disease (BD). Apremilast is an inhibitor of phosphodi-esterase-4, an enzyme involved in the pathogenesis of several dermatologic conditions. This review explores the potential utility of apremilast in the treatment of other unapproved dermatologic indications.
Subject(s)
Thalidomide , Humans , Thalidomide/analogs & derivatives , Thalidomide/therapeutic use , Behcet Syndrome/drug therapy , Psoriasis/drug therapy , Anti-Inflammatory Agents, Non-Steroidal/therapeutic use , Tablets , Arthritis, Psoriatic/drug therapyABSTRACT
BACKGROUND: To evaluate the risk of neutropenia during treatment with anti-IL-23 antibodies in patients with psoriasis. METHOD: We conducted an observational study with cohort design using MID-NET® in Japan. We identified patients with psoriasis who were newly prescribed anti-IL-23 antibodies, anti-IL-17-antibodies, adalimumab, or apremilast between January 1, 2009, and March 31, 2021. We estimated the adjusted hazard ratio (aHR) of anti-IL-23 antibodies compared to that of anti-IL-17 antibodies, adalimumab, or apremilast, for the risk of grade 2 (neutrophil count < 1,500/µL) or grade 3 (neutrophil count < 1,000/µL) neutropenia. RESULTS: Overall, 287 patients on anti-IL-23 antibodies, 189 patients on anti-IL-17 antibodies, 293 patients on adalimumab, and 540 patients on apremilast were included. Compared with anti-IL-17 antibodies, the aHR (95% confidence interval (CI)) of anti-IL-23 antibodies was 0.83 (0.27-2.51) for grade 2 and 0.40 (0.02-7.60) for grade 3 neutropenia; that when compared with adalimumab was 0.76 (0.28-2.06) for grade 2 but was not calculated for grade 3 as no cases were found; and that compared with apremilast was 3.88 (0.62-24.48) for grade 2 and 0.43 (0.02-11.63) for grade 3 neutropenia. CONCLUSION: No clear increase in the risk of neutropenia with anti-IL-23 antibodies was observed.
Subject(s)
Adalimumab , Interleukin-17 , Interleukin-23 , Neutropenia , Psoriasis , Thalidomide , Humans , Adalimumab/adverse effects , Adalimumab/immunology , Psoriasis/drug therapy , Psoriasis/immunology , Female , Male , Neutropenia/chemically induced , Neutropenia/immunology , Neutropenia/epidemiology , Middle Aged , Japan , Adult , Interleukin-17/antagonists & inhibitors , Interleukin-17/immunology , Interleukin-23/antagonists & inhibitors , Interleukin-23/immunology , Thalidomide/adverse effects , Thalidomide/analogs & derivatives , Aged , Antibodies, Monoclonal, Humanized/adverse effectsABSTRACT
Introduction: Although the treatment for pemphigus vulgaris (PV) has been revolutionized by the use of rituximab combined with corticosteroids, new effective therapies with a better safety profile are needed. Observation: A 67-year-old woman was diagnosed with severe mucosal PV, which was initially misdiagnosed as atypical Behçet's disease. Following an unsuccessful colchicine treatment, significant improvement was observed upon the introduction of apremilast: reduced pain, fewer lesions, and a stabilized weight. The discontinuation of apremilast led to a rapid relapse. Retrospective analysis through anti-Dsg3 ELISA indicated a gradual decrease in antibody levels during the apremilast treatment. Discussion: Apremilast, a phosphodiesterase 4 inhibitor approved for psoriasis and Behçet's disease's related oral ulcers treatment, demonstrated its efficacy in this PV case. This is the second case report highlighting the effectiveness of apremilast for PV treatment. Apremilast's ability to upregulate cyclic adenosine monophosphate (cAMP) levels appears to contribute to the stabilization of keratinocyte adhesion. Conclusion: Apremilast may be a promising therapeutic option for the treatment of pemphigus, with an innovative mechanism of action, no induced immunosuppression, and good tolerance. It could be a good alternative to steroids, in the treatment regimen of steroids combined with rituximab.
Subject(s)
Pemphigus , Thalidomide , Humans , Pemphigus/drug therapy , Pemphigus/diagnosis , Female , Thalidomide/analogs & derivatives , Thalidomide/therapeutic use , Aged , Treatment Outcome , Anti-Inflammatory Agents, Non-Steroidal/therapeutic use , Phosphodiesterase 4 Inhibitors/therapeutic useABSTRACT
BACKGROUND: The immunomodulatory imide drugs (IMiDs) thalidomide, lenalidomide and pomalidomide may exhibit therapeutic efficacy in the prostate. In lower urinary tract symptoms (LUTS), voiding and storage disorders may arise from benign prostate hyperplasia, or overactive bladder. While current therapeutic options target smooth muscle contraction or cell proliferation, side effects are mostly cardiovascular. Therefore, we investigated effects of IMiDs on human detrusor and porcine artery smooth muscle contraction, and growth-related functions in detrusor smooth muscle cells (HBdSMC). METHODS: Cell viability was assessed by CCK8, and apoptosis and cell death by flow cytometry in cultured HBdSMC. Contractions of human detrusor tissues and porcine interlobar and coronary arteries were induced by contractile agonists, or electric field stimulation (EFS) in the presence or absence of an IMID using an organ bath. Proliferation was assessed by EdU assay and colony formation, cytoskeletal organization by phalloidin staining, RESULTS: Depending on tissue type, IMiDs inhibited cholinergic contractions with varying degree, up to 50â¯%, while non-cholinergic contractions were inhibited up to 80â¯% and 60â¯% for U46619 and endothelin-1, respectively, and EFS-induced contractions up to 75â¯%. IMiDs reduced viable HBdSM cells in a time-dependent manner. Correspondingly, proliferation was reduced, without showing pro-apoptotic effects. In parallel, IMiDs induced cytoskeletal disorganization. CONCLUSIONS: IMiDs exhibit regulatory functions in various smooth muscle-rich tissues, and of cell proliferation in the lower urinary tract. This points to a novel drug class effect for IMiDs, in which the molecular mechanisms of action of IMiDs merit further consideration for the application in LUTS.
Subject(s)
Cell Proliferation , Muscle Contraction , Myocytes, Smooth Muscle , Urinary Bladder , Humans , Muscle Contraction/drug effects , Cell Proliferation/drug effects , Urinary Bladder/drug effects , Myocytes, Smooth Muscle/drug effects , Animals , Swine , Male , Thalidomide/pharmacology , Thalidomide/analogs & derivatives , Muscle, Smooth/drug effects , Immunomodulating Agents/pharmacology , Cells, Cultured , Apoptosis/drug effects , Cell Survival/drug effects , Lenalidomide/pharmacologyABSTRACT
BACKGROUND: Central nervous system involvement in chronic lymphocytic leukemia rarely occurs, and there is no standard therapy for central nervous system involvement in chronic lymphocytic leukemia. This article aims to analyze the diagnosis and treatment of central nervous system involvement in chronic lymphocytic leukemia. CASE PRESENTATION: It reports two cases of central nervous system involvement in chronic lymphocytic leukemia describing the clinical course, therapy, and prognosis. Case 1 is a 67-year-old Asian male patient, he experienced complications with central nervous system involvement after developing resistance to ibrutinib, bendamustine, and rituximab (BR) chemotherapies. The central nervous system lesion was controlled with high-dose methotrexate combined with pomalidomide, but Richter transformation occurred several months later. Case 2 is a 62-year-old Asian female patient, she had central nervous system involvement at initial diagnosis, and bone marrow and central nervous system lesions were controlled by ibrutinib therapy. CONCLUSION: Central nervous system involvement in chronic lymphocytic leukemia is rare and can be diagnosed on the basis of clinical features, cerebrospinal fluid testing, and radiographic evaluation. Ibrutinib, pomalidomide, and other drugs that can cross the blood-brain barrier may be effective for treating central nervous system involvement in chronic lymphocytic leukemia.
Subject(s)
Adenine , Leukemia, Lymphocytic, Chronic, B-Cell , Piperidines , Thalidomide , Humans , Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy , Aged , Male , Female , Middle Aged , Adenine/analogs & derivatives , Piperidines/therapeutic use , Thalidomide/therapeutic use , Thalidomide/analogs & derivatives , Central Nervous System Neoplasms/drug therapy , Central Nervous System Neoplasms/secondary , Central Nervous System Neoplasms/diagnostic imaging , Pyrazoles/therapeutic use , Methotrexate/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Pyrimidines/therapeutic useABSTRACT
BACKGROUND/PURPOSE: The treatment landscape of relapsed/refractory multiple myeloma (RRMM) is rapidly evolving in Taiwan. The present study aimed to assess the treatment patterns among RRMM patients in Taiwan. METHODS: This retrospective, chart review-based, non-interventional study collected data on RRMM patients (≥20 years old) receiving pomalidomide-based treatment between January 2017 and December 2020 across five sites in Taiwan. RESULTS: Median age of the study population was 65.6 years. Approximately 75% patients received a doublet regimen and 25% were on a triplet regimen. Disease progression was the most common cause for switching to pomalidomide-based treatments in doublet (71.2%) and triplet (58.3%) groups. Patients in doublet and triplet groups (>80%) received 4 mg pomalidomide as a starting dose. Overall response rate (ORR: 31.5% and 45.8%) and median progression-free survival (PFS: 4.7 and 6.8 months) were reported in the doublet and triplet regimen. Doublet regimen was discontinued mainly due to disease progression or death (78.1%); however, triplet regimen patients mainly terminated their treatment due to reimbursement limitations (29.2%). Healthcare resource utilization (HRU) was comparable between doublet and triplet groups. CONCLUSION: In Taiwan, half of RRMM patients received pomalidomide-based triplet regimens. Triplet regimens showed a trend towards better outcomes with longer PFS and higher response rates compared to doublets. Notably, the duration of triplet use is influenced by reimbursement limitations. This study provides insight into RRMM treatment patterns in Taiwan and the findings suggest that triplet regimens may be a better alternative than doublet regimens.
Subject(s)
Multiple Myeloma , Thalidomide , Humans , Multiple Myeloma/drug therapy , Multiple Myeloma/mortality , Thalidomide/analogs & derivatives , Thalidomide/therapeutic use , Thalidomide/administration & dosage , Aged , Female , Male , Taiwan , Retrospective Studies , Middle Aged , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Aged, 80 and over , Adult , RecurrenceABSTRACT
INTRODUCTION: The treatment of multiple myeloma (MM) is evolving rapidly. Quadruplet regimens incorporating proteasome inhibitors, immunomodulatory drugs (IMiDs), and CD38 monoclonal antibodies have emerged as standard-of-care options for newly diagnosed MM, and numerous novel therapies have been approved for relapsed/refractory MM. However, there remains a need for novel options in multiple settings, including refractoriness to frontline standards of care. AREAS COVERED: Targeting degradation of IKZF1 and IKZF3 - Ikaros and Aiolos - through modulation of cereblon, an E3 ligase substrate recruiter/receptor, is a key mechanism of action of the IMiDs and the CELMoD agents. Two CELMoD agents, iberdomide and mezigdomide, have demonstrated substantial preclinical and clinical activity in MM and have entered phase 3 investigation. Using a literature search methodology comprising searches of PubMed (unlimited time-frame) and international hematology/oncology conference abstracts (2019-2023), this paper reviews the importance of Ikaros and Aiolos in MM, the mechanism of action of the IMiDs and CELMoD agents and their relative potency for targeting Ikaros and Aiolos, and preclinical and clinical data on iberdomide and mezigdomide. EXPERT OPINION: Emerging data suggest that iberdomide and mezigdomide have promising activity, including in IMiD-resistant settings and, pending phase 3 findings, may provide additional treatment options for patients with MM.
Subject(s)
Ikaros Transcription Factor , Multiple Myeloma , Thalidomide , Humans , Multiple Myeloma/drug therapy , Multiple Myeloma/metabolism , Ikaros Transcription Factor/metabolism , Thalidomide/therapeutic use , Thalidomide/analogs & derivatives , Thalidomide/pharmacology , Signaling Lymphocytic Activation Molecule Family/metabolism , Signaling Lymphocytic Activation Molecule Family/antagonists & inhibitors , Ubiquitin-Protein Ligases/metabolism , Antineoplastic Agents/therapeutic use , Antineoplastic Agents/pharmacology , Proteolysis/drug effects , Molecular Targeted Therapy , Immunomodulating Agents/therapeutic use , Immunomodulating Agents/pharmacology , Clinical Trials as Topic , Animals , Piperidones , Morpholines , Receptors, Interleukin-17 , Adaptor Proteins, Signal Transducing , PhthalimidesABSTRACT
OBJECTIVE: The objective of this study was to investigate the therapeutic efficacy of thalidomide across various genotype presentations of ß-thalassemia so as to facilitate the early screening of thalidomide-sensitive thalassemia cases and to understand the impact of iron overload on thalidomide. METHODS: From our initial sample of 52 patients, we observed 48 patients with ß-thalassemia for two years after administration of thalidomide. This cohort included 34 patients with transfusion-dependent thalassemia (TDT) and 14 patients with non-transfusion-dependent thalassemia (NTDT). We recorded the values of hemoglobin (Hb), fetal hemoglobin (HbF), and serum ferritin (SF) in the baseline period and at 1, 3, 6, 12, 18, and 24 months after enrollment, as well as the pre- and post-treatment blood transfusion volume in all 48 cases. According to the increase in Hb levels from baseline during the 6-month observation period, the response to thalidomide was divided into four levels: main response (MaR), minor response (MiR), slow response (SLR), and no response (NR). A decrease in serum ferritin levels compared to baseline was considered alleviation of iron overload. We calculated the overall response rate (ORR) as follows: ORR = MaR + MiR + SLR/number of observed cases. RESULTS: The ORR was 91.7% (44/48 cases), and 72.9% showed MaR (35/48 cases). Among the 34 patients with TDT, 21 patients (61.8%) were free of blood transfusion, and the remaining 13 patients still required blood transfusion, but their total blood transfusion volume reduced by 31.3% when compared to the baseline. We found a total of 33 cases with 10 combinations of advantageous genes, which included 5 cases with ßCD41-42/ßCD17 and 6 cases with ßCD41-42/ß-28. Based on the treatment outcomes among the 48 cases in the observation group, there were 33 cases in the MaR group and 15 cases in the SLR/NR group. There was a difference in HbF between the two groups at baseline (P = 0.041). There were significant differences between the two groups in Hb and HbF at the time points of 6 and 12 months, respectively (P < 0.001). Compared to the baseline measurement, there was a significant decrease in the level of SF at months 12 and 24 (P < 0.001). CONCLUSION: In this study, we identified 10 ß-thalassemia gene combinations that were sensitive to thalidomide. These gene combinations can be used for initial screening and to predict the therapeutic effect of thalidomide in clinical practice. We examined the therapeutic response to thalidomide and found that the administration of thalidomide in combination with standardized iron removal was more beneficial in reducing iron overload.
Subject(s)
Genotype , Thalidomide , beta-Thalassemia , Humans , Thalidomide/therapeutic use , beta-Thalassemia/drug therapy , beta-Thalassemia/genetics , beta-Thalassemia/blood , Female , Male , Adult , Treatment Outcome , Adolescent , Child , Ferritins/blood , Young Adult , Blood Transfusion , Child, Preschool , Fetal Hemoglobin/genetics , Iron Overload/drug therapy , Iron Overload/geneticsABSTRACT
BACKGROUND: Polyneuropathy, organomegaly, endocrinopathy, M-protein, and skin changes (POEMS) syndrome is a rare plasma cell (PC) neoplasm with associated paraneoplastic syndrome. According to the current diagnostic criteria, peripheral polyneuropathy and monoclonal PC proliferative disorder represent two mandatory criteria. CASE PRESENTATION: We report a 54-year-old male with peripheral neuropathy of bilateral lower limbs, sclerotic bone lesions, elevated vascular endothelial growth factor (VEGF) levels, splenomegaly, extravascular volume overload, endocrinopathy, and skin hemangiomas. Of note, serum and urine protein electrophoresis (PEP) and immunofixation electrophoresis (IFE) of this patient indicated undetectable M-protein and the normal ratio of free light chains κ and λ (FLC-R (κ/λ)). No monoclonal PCs were found in bone marrow examinations or biopsy of diseased bones. However, his clinical manifestations matched most of the diagnostic criteria. After excluding other diseases that are easily confused with POEMS syndrome, the diagnosis of variant POEMS syndrome with undetectable M-protein was proposed. The patient obtained clinically significant improvement and elevated VEGF returned to normal after 6 months of treatment with lenalidomide plus dexamethasone. CONCLUSIONS: Monoclonal PC dyscrasia (M-protein) while being a mandatory criterion for POEMS syndrome is undetectable in a considerable amount of patients that otherwise demonstrate typical symptoms. Here, we reported a case of variant POEMS syndrome with featured clinical manifestations, elevated VEGF levels, and good response to therapies targeting PCs but no evidence of M-protein. Therefore, negative results in M-protein and monoclonal PCs aren't enough to reject the diagnosis of POEMS syndrome. It is imperative to recognize the variant form of POEMS syndrome.
Subject(s)
POEMS Syndrome , Humans , POEMS Syndrome/diagnosis , POEMS Syndrome/pathology , Male , Middle Aged , Lenalidomide/therapeutic use , Thalidomide/therapeutic use , Thalidomide/analogs & derivatives , Vascular Endothelial Growth Factor A , Dexamethasone/therapeutic use , Treatment Outcome , Myeloma Proteins/analysisABSTRACT
Multiple myeloma (MM) is a haematological lymphoid malignancy involving tumoural plasma cells and is usually characterized by the presence of a monoclonal immunoglobulin protein. MM is the second most common haematological malignancy, with an increasing global incidence. It remains incurable because most patients relapse or become refractory to treatments. MM is a genetically complex disease with high heterogeneity that develops as a multistep process, involving acquisition of genetic alterations in the tumour cells and changes in the bone marrow microenvironment. Symptomatic MM is diagnosed using the International Myeloma Working Group criteria as a bone marrow infiltration of ≥10% clonal plasma cells, and the presence of at least one myeloma-defining event, either standard CRAB features (hypercalcaemia, renal failure, anaemia and/or lytic bone lesions) or biomarkers of imminent organ damage. Younger and fit patients are considered eligible for transplant. They receive an induction, followed by consolidation with high-dose melphalan and autologous haematopoietic cell transplantation, and maintenance therapy. In older adults (ineligible for transplant), the combination of daratumumab, lenalidomide and dexamethasone is the preferred option. If relapse occurs and requires further therapy, the choice of therapy will be based on previous treatment and response and now includes immunotherapies, such as bi-specific monoclonal antibodies and chimeric antigen receptor T cell therapy.
Subject(s)
Multiple Myeloma , Multiple Myeloma/therapy , Multiple Myeloma/physiopathology , Multiple Myeloma/diagnosis , Multiple Myeloma/epidemiology , Humans , Dexamethasone/therapeutic use , Lenalidomide/therapeutic use , Antibodies, Monoclonal/therapeutic use , Hematopoietic Stem Cell Transplantation/methods , Melphalan/therapeutic use , Thalidomide/therapeutic use , Thalidomide/analogs & derivatives , Antineoplastic Combined Chemotherapy Protocols/therapeutic useABSTRACT
Based on the lack of differences in progression-free and overall survival after a median follow-up of 93 months in our HOVON-65/GMMG-HD4 trial (German part; n = 395) randomizing VAD induction (vincristin/adriamycin/dexamthasone)/tandem-transplantation/thalidomide-maintenance vs. PAD induction (bortezomib/adriamycin/dexamethasone)/tandem transplantation/bortezomib maintenance, we discern how chromosomal aberrations determine long-term prognosis by different patterns of association with proliferation and treatment-dependent response, whether responses achieved by different regimens are equal regarding prognosis, and whether subpopulations of patients could be defined as treatable without upfront "novel agents" in cases of limited resources, e.g., in low- or middle-income countries. Serum parameters and risk factors were assessed in 395 patients. CD138-purified plasma cells were subjected to fluorescence in situ hybridization (n = 354) and gene expression profiling (n = 204). We found chromosomal aberrations to be associated in four patterns with survival, proliferation, and response: deletion (del) del17p13, del8p21, del13q14, (gain) 1q21+, and translocation t(4;14) (all adverse) associate with higher proliferation. Of these, del17p is associated with an adverse response (pattern 1), and 1q21+, t(4;14), and del13q14 with a treatment-dependent better response (pattern 2). Hyperdiploidy associates with lower proliferation without impacting response or survival (pattern 3). Translocation t(11;14) has no association with survival but a treatment-dependent adverse response (pattern 4). Significantly fewer patients reach a near-complete response or better with "conventional" (VAD) vs. bortezomib-based treatment after induction or high-dose melphalan. These patients, however, show significantly better median progression-free and overall survival. Molecularly, patients responding to the two regimens differ in gene expression, indicating distinct biological properties of the responding myeloma cells. Patients with normal renal function (89.4%), low cytogenetic risk (72.5%), or low proliferation rate (37.9%) neither benefit in progression-free nor overall survival from bortezomib-based upfront treatment. We conclude that response level, the treatment by which it is achieved, and molecular background determine long-term prognosis. Chromosomal aberrations are associated in four patterns with proliferation and treatment-dependent responses. Associations with faster and deeper responses can be deceptive in the case of prognostically adverse aberrations 1q21+ and t(4;14). Far from advocating a return to "outdated" treatments, if resources do not permit state-of-the-art-treatment, normal renal function and/or molecular profiling identifies patient subpopulations doing well without upfront "novel agents".
Subject(s)
Chromosome Aberrations , Multiple Myeloma , Humans , Multiple Myeloma/genetics , Multiple Myeloma/drug therapy , Multiple Myeloma/mortality , Multiple Myeloma/pathology , Female , Male , Middle Aged , Aged , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Cell Proliferation/drug effects , Prognosis , Adult , Developing Countries , Dexamethasone/therapeutic use , Dexamethasone/pharmacology , Bortezomib/therapeutic use , Bortezomib/pharmacology , Thalidomide/therapeutic useABSTRACT
Immunomodulatory imide drugs (IMiDs) play a crucial role in the treatment landscape across various stages of multiple myeloma. Despite their evident efficacy, some patients may exhibit primary resistance to IMiD therapy, and acquired resistance commonly arises over time leading to inevitable relapse. It is critical to develop novel therapeutic options to add to the treatment arsenal to overcome IMiD resistance. We designed, synthesized, and screened a new class of polyfluorinated thalidomide analogs and investigated their anti-cancer, anti-angiogenic, and anti-inflammatory activity using in vitro and ex vivo biological assays. We identified four lead compounds that exhibit potent anti-myeloma, anti-angiogenic, anti-inflammatory properties using three-dimensional tumor spheroid models, in vitro tube formation, and ex vivo human saphenous vein angiogenesis assays, as well as the THP-1 inflammatory assay. Western blot analyses investigating the expression of proteins downstream of cereblon (CRBN) reveal that Gu1215, our primary lead candidate, exerts its activity through a CRBN-independent mechanism. Our findings demonstrate that the lead compound Gu1215 is a promising candidate for further preclinical development to overcome intrinsic and acquired IMiD resistance in multiple myeloma.
Subject(s)
Drug Resistance, Neoplasm , Multiple Myeloma , Thalidomide , Multiple Myeloma/drug therapy , Multiple Myeloma/pathology , Humans , Thalidomide/analogs & derivatives , Thalidomide/pharmacology , Thalidomide/chemistry , Drug Resistance, Neoplasm/drug effects , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemistry , Antineoplastic Agents/chemical synthesis , Angiogenesis Inhibitors/pharmacology , Angiogenesis Inhibitors/chemistry , Cell Line, Tumor , Anti-Inflammatory Agents/pharmacology , Anti-Inflammatory Agents/chemistry , Drug Evaluation, PreclinicalABSTRACT
Objective: This study compared the pharmacokinetics, safety and bioequivalence (BE) of generic and original apremilast tablets in healthy Chinese subjects under fasting and postprandial conditions, providing sufficient evidence for abbreviated new drug application. Methods: A randomized, open-label, two-formulation, single-dose, two-period crossover pharmacokinetic study was performed. Thirty-two eligible healthy Chinese subjects were enrolled in fasting and postprandial studies, respectively. In each trial, subjects received a single 30-mg dose of the test or reference apremilast tablet, followed by a 7-day washout interval between periods. Serial blood samples were obtained for up to 48 h post-intake in each period, and the plasma concentrations of apremilast were determined by a validated method. The primary pharmacokinetic (PK) parameters, including the maximum plasma concentration (Cmax), the areas under the plasma concentration-time curve (AUC0-t, AUC0-∞), were calculated using the non-compartmental method. The geometric mean ratios of the two formulations and the corresponding 90% confidence intervals (CIs) were acquired for bioequivalence analysis. The safety of both formulations was also evaluated. Results: Under fasting and postprandial states, the PK parameters of the test drug were similar to those of the reference drug. The 90% CIs of the geometric mean ratios of the test to reference formulations were 94.09-103.44% for Cmax, 94.05-103.51% for AUC0-t, and 94.56-103.86% for AUC0-∞ under fasting conditions, and 99.18-112.48% for Cmax, 98.79-106.02% for AUC0-t, and 98.95-105.89% for AUC0-∞ under postprandial conditions, all of which were within the bioequivalence range of 80.00-125.00%. Both formulations were well tolerated, and no serious adverse events occurred during the study. Conclusion: The trial confirmed that the PK parameters of the generic and original apremilast tablets were bioequivalent in healthy Chinese subjects under fasting and postprandial states, which met the predetermined regulatory standards. Both formulations were safe and well tolerated. Clinical Trial Registration: chinaDrugtrials.org.cn, identifier CTR20191056 (July 30, 2019); chictr.org.cn, identifier ChiCTR2300076806 (October 19, 2023).
Subject(s)
Cross-Over Studies , Fasting , Healthy Volunteers , Postprandial Period , Tablets , Thalidomide , Therapeutic Equivalency , Humans , Thalidomide/analogs & derivatives , Thalidomide/pharmacokinetics , Thalidomide/administration & dosage , Thalidomide/blood , Adult , Male , Young Adult , Female , Anti-Inflammatory Agents, Non-Steroidal/pharmacokinetics , Anti-Inflammatory Agents, Non-Steroidal/administration & dosage , Anti-Inflammatory Agents, Non-Steroidal/blood , Asian People , Area Under Curve , Administration, OralABSTRACT
We previously showed that the PDE4 inhibitor apremilast reduces ethanol consumption in mice by protein kinase A (PKA) and GABAergic mechanisms. Preventing PKA phosphorylation of GABAA ß3 subunits partially blocked apremilast-mediated decreases in drinking. Here, we produced Gabrb1-S409A mice to render GABAA ß1 subunits resistant to PKA-mediated phosphorylation. Mass spectrometry confirmed the presence of the S409A mutation and lack of changes in ß1 subunit expression or phosphorylation at other residues. ß1-S409A male and female mice did not differ from wild-type C57BL/6J mice in expression of Gabrb1, Gabrb2, or Gabrb3 subunits or in behavioral characteristics. Apremilast prolonged recovery from ethanol ataxia to a greater extent in Gabrb1-S409A mice but prolonged recovery from zolpidem and propofol to a similar extent in both genotypes. Apremilast shortened recovery from diazepam ataxia in wild-type but prolonged recovery in Gabrb1-S409A mice. In wild-type mice, the PKA inhibitor H89 prevented apremilast modulation of ataxia by ethanol and diazepam, but not by zolpidem. In Gabrb1-S409A mice, inhibiting PKA or EPAC2 (exchange protein directly activated by cAMP) partially reversed apremilast potentiation of ethanol, diazepam, and zolpidem ataxia. Apremilast prevented acute tolerance to ethanol ataxia in both genotypes, but there were no genotype differences in ethanol consumption before or after apremilast. In contrast to results in Gabrb3-S408A/S409A mice, PKA phosphorylation of ß1-containing GABAA receptors is not required for apremilast's effects on acute tolerance or on ethanol consumption but is required for its ability to decrease diazepam intoxication. Besides PKA we identified EPAC2 as an additional cAMP-dependent mechanism by which apremilast regulates responses to GABAergic drugs.