Natural History Study of Idiopathic Multicentric Castleman Disease Identifies Effective Treatments for a Large Proportion of Patients but Treatment-Refractory Patients Remain

Background Human herpes-virus 8-negative/idiopathic multicentric Castleman disease (iMCD) is a rare inflammatory disorder involving multicentric lymphadenopathy with characteristic histopathology. Clinical presentation is heterogenous and includes cytokine-driven constitutional symptoms, cytopenias, systemic inflammation, and multi-organ dysfunction. International consensus treatment guidelines are based on a large cohort of case studies and a few clinical trials, but the available evidence is limited. Siltuximab, an anti-IL-6 therapy, is the only FDA-approved treatment for iMCD; 34% of patients achieved durable symptomatic and tumor response in the phase II trial. Tocilizumab, an anti-IL-6 receptor therapy, is frequently used off label and demonstrated promising results in an open-label study in Japan. The treatment guidelines recommend siltuximab ± corticosteroids (CS) as first-line therapy for all iMCD patients and tocilizumab as a substitute when siltuximab is not available. Rituximab, a CD20 antibody, is recommended as an alternate first-line therapy in patients who are non-severe and do not exhibit marked cytokine-driven symptoms. In all other patients, rituximab is recommended second-line; however, it has never been systematically evaluated in iMCD. Chemotherapies, immunosuppressants, and immunomodulators are recommended second- or third-line, but again, effectiveness is not well described. Better understanding of treatment effectiveness is urgently needed. Herein, we describe treatment and response in a real-world cohort of iMCD patients. Methods Data were collected and abstracted for 68 patients enrolled in an on-going IRB-approved natural history study of Castleman disease. Diagnosis is graded by an expert panel of clinicians and pathologists on an on-going basis; patients unlikely to have iMCD were excluded from analysis (N=12). Of the 56 patients included, 37 (66%) are expert panel-confirmed and 19 (34%) are awaiting confirmation. Durable response is defined as achieving ≥50% improvement in the proportion of abnormal iMCD minor clinical and laboratory diagnostic criteria sustained for ≥1 year. Small sample size prevented statistical comparisons. Results Median age at diagnosis is 33 years (range: 1-65 years). The cohort is 52.9% female, 63% white, and 4 (7%) patients died. Thirty-three unique drugs, including anti-IL-6 therapies, CS, chemotherapies, immunosuppressants, and others have been administered across the 56 patients. Rituximab is the most frequently used drug, administered to 39 (70%) patients. Siltuximab (29 patients, 52%) and tocilizumab (19 patients, 34%) are the next two most frequently used targeted therapies. There was a 52% response (15/29) to regimens inclusive of siltuximab, 50% response (9/18) to those inclusive of tocilizumab, and 25% response (9/26) to those inclusive of rituximab. Siltuximab±CS induced response in 15/24 (63%) patients, tocilizumab±CS in 4/7 (57%), and rituximab±CS in 2/13 (15%). Among the 37 expert-confirmed iMCD patients, we found a 58% response (11/19) to regimens inclusive of siltuximab, 47% (8/17) to those inclusive of tocilizumab, and 27% (7/26) to those inclusive of rituximab. Further, in these patients, siltuximab±CS induced response in 11/16 (69%), tocilizumab±CS in 3/6 (50%), and rituximab±CS in 1/6 (17%) patients. Of note, 3 of 4 deceased patients received both anti-IL-6 therapy and rituximab and all 4 received chemotherapies and immunosuppressants but did not respond to any drug. Discussion These data reveal that despite there being one FDA-approved treatment, iMCD is treated with a variety of agents. Among the full cohort, siltuximab±CS demonstrated a 63% durable response, which was higher than the response reported in the clinical trial (not statistically compared). This may reflect differences in response criteria and/or disease activity of patients in clinical trials versus real world settings. Siltuximab and tocilizumab have never been systematically compared; in this cohort they demonstrated similar response. Considering the morbidity and mortality of iMCD, these data suggest that current therapies demonstrate important activity. However, additional agents are needed for refractory patients, who have few options and are at risk of death due to disease progression. Further data are needed to compare groups and identify optimal treatment protocols. Disclosures Liu: BridgeBio Pharma: Employment, Equity Ownership. Gibson:EUSA Pharma: Employment. Kanhai:EUSA Pharma: Employment. Martin:EUSA Pharma: Employment. Srkalovic:Takeda: Speakers Bureau; Janssen: Speakers Bureau; Foundation Medicine: Speakers Bureau; EUSA Pharma: Speakers Bureau. Uldrick:Patent: Patents & Royalties: co-inventor on US Patent 10,001,483 entitled ; Celgene: Other: research support from Celgene through a CRADA at the NCI; Roche: Other: commercial research support through a CTA with Fred Hutchinson Cancer Research Center; Merck: Other: drug for a clinical trial from Merck through a CRADA with the NCI. van Rhee:Takeda: Consultancy; Sanofi Genzyme: Consultancy; Karyopharm Therapeutics: Consultancy; EUSA: Consultancy; Adicet Bio: Consultancy; Kite Pharma: Consultancy; Castleman Disease Collaborative Network: Consultancy. Fajgenbaum:Janssen Pharmaceuticals: Research Funding. OffLabel Disclosure: Tocilizumab, a monoclonal antibody directed against IL-6-receptor, is approved for use in rheumatoid arthritis in the US. It is frequently used off-label in idiopathic multicentric Castleman disease (iMCD) and is recommended as a substitute first-line therapy in the International Consensus iMCD treatment guidelines. Rituximab, a monoclonal antibody directed against CD20, is used in rheumatoid arthritis and other autoimmune and cancerous disorders. It is frequently used off-label in iMCD and is recommended as an alternate first-line or a second-line therapy in the International Consensus iMCD treatment guidelines. Corticosteroids are used broadly in iMCD and are recommended as needed as useful adjunctive therapy in the International Consensus iMCD treatment guidelines.

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Antiepileptic and Antidepressant Drugs Used in the Treatment of Pain

10.2310/pm.15092 ◽

2017 ◽

Author(s):

Lucia Daiana Voiculescu

Keyword(s):

Serotonin Syndrome ◽

Molecular Mechanisms ◽

Tricyclic Antidepressants ◽

Antidepressant Drugs ◽

First Line ◽

Off Label ◽

First Line Therapy ◽

Line Therapy ◽

Pain Pathways ◽

Different Levels

Antiepileptics and antidepressants are two categories of drugs frequently used as adjuvant analgesics. They interfere with the pain pathways at different levels through complex and not always well-defined molecular mechanisms. Although only a few have been licensed for use in the treatment of certain types of pain, anticonvulsants and antidepressants are widely prescribed off-label for pain associated with a variety of conditions. Most solid data come from experience with their use for postherpetic neuralgia, pain associated with diabetic neuropathy, and fibromyalgia. Anticonvulsants and antidepressant drugs are frequently used as first-line therapy in the treatment of pain, especially neuropathic type. Key words: antidepressant drugs, antiepileptic drugs, carbamazepine, gabapentinoids, neuropathic pain, off-label use, serotonin-norepinephrine reuptake inhibitors, serotonin syndrome, tricyclic antidepressants, use in specific populations

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Immune Checkpoint Inhibitors for the Treatment of Bladder Cancer

Cancers ◽

10.3390/cancers13010131 ◽

2021 ◽

Vol 13 (1) ◽

pp. 131

Author(s):

Antonio Lopez-Beltran ◽

Alessia Cimadamore ◽

Ana Blanca ◽

Francesco Massari ◽

Nuno Vau ◽

...

Keyword(s):

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Objective Response ◽

Line Treatment ◽

Second Line ◽

First Line ◽

Durable Response ◽

First Line Therapy ◽

Line Therapy

A number of immune checkpoint inhibitors (ICIs) have been approved as first-line therapy in case of cisplatin-ineligible patients or as second-line therapy for patients with metastatic urothelial carcinoma (mUC) of the bladder. About 30% of patients with mUC will respond to ICIs immunotherapy. Programmed death-ligand 1 (PD-L1) expression detected by immunohistochemistry seems to predict response to immune checkpoint inhibitors in patients with mUC as supported by the objective response rate (ORR) and overall survival (OS) associated with the response observed in most clinical trials. Pembrolizumab, an anti-PD-1 antibody, demonstrated better OS respective to chemotherapy in a randomized phase 3 study for second-line treatment of mUC. Nivolumab, a PD-1 antibody, also demonstrated an OS benefit when compared to controls. Atezolizumab, Durvalumab, and Avelumab antibodies targeting PD-L1 have also received approval as second-line treatments for mUC with durable response for more than 1 year in selected patients. Atezolizumab and Pembrolizumab also received approval for first-line treatment of patients that are ineligible for cisplatin. A focus on the utility of ICIs in the adjuvant or neoadjuvant setting, or as combination with chemotherapy, is the basis of some ongoing trials. The identification of a clinically useful biomarker, single or in association, to determine the optimal ICIs treatment for patients with mUC is very much needed as emphasized by the current literature. In this review, we examined relevant clinical trial results with ICIs in patients with mUC alone or as part of drug combinations; emphasis is also placed on the adjuvant and neoadjuvant setting. The current landscape of selected biomarkers of response to ICIs including anti-PD-L1 immunohistochemistry is also briefly reviewed.

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Progress and Challenges of Integrated Drug Efficacy Surveillance for Uncomplicated Malaria in Thailand

10.21203/rs.3.rs-343048/v1 ◽

2021 ◽

Author(s):

Prayuth Sudathip ◽

Aungkana Saejeng ◽

Nardlada Khantikul ◽

Thannikar Thongrad ◽

Suravadee Kitchakarn ◽

...

Keyword(s):

System Integration ◽

Treatment Guidelines ◽

Drug Efficacy ◽

Fiscal Year ◽

Efficacy Rate ◽

First Line ◽

First Line Therapy ◽

Line Therapy ◽

Kaplan Meier ◽

History Of

Abstract BackgroundIntegrated drug efficacy surveillance (iDES) was formally introduced nationally across Thailand in fiscal year 2018 (FY2018), building on a history of drug efficacy monitoring and interventions. According to the National Malaria Elimination Strategy for Thailand 2017–2026, diagnosis is microscopically confirmed, treatment is prescribed, and patients are followed up four times to ensure cure.MethodsRoutine patient data were extracted from the malaria information system for FY2018–FY2020. Treatment failure of first-line therapy was defined as confirmed parasite reappearance within 42 days for Plasmodium falciparum and 28 days for Plasmodium vivax. The primary outcome was the crude drug efficacy rate, estimated using Kaplan–Meier methods, at day 42 for P. falciparum treated with dihydroartemisinin-piperaquine plus primaquine, and day 28 for P. vivax treated with chloroquine plus primaquine; day 60 and day 90 efficacy were secondary outcomes for P. vivax.ResultsThe proportion of patients with outcomes recorded at day 42 for P. falciparum malaria and at day 28 for P. vivax malaria has been increasing, with FY2020 follow-up rates of 61.5% and 57.2%, respectively. For P. falciparum malaria, day 42 efficacy in FY2018 was 92.4% (n = 249), in FY2019 93.3% (n = 379), and in FY2020 98.0% (n = 167). P. falciparum recurrences occurred disproportionally in Sisaket Province, with day 42 efficacy rates of 75.9% in FY2018 (n = 59) and 49.4% in FY2019 (n = 49), leading to an update in first-line therapy to pyronaridine-artesunate at the provincial level, rolled out in FY2020. For P. vivax malaria, day 28 efficacy was 98.5% in FY2018 (n = 2,048), 99.1% in FY2019 (n = 2,206), and 99.9% in FY2020 (n = 2,448), and day 90 efficacy was 94.8%, 96.3%, and 97.1%, respectively.ConclusionsIn Thailand, iDES provided operationally relevant data on drug efficacy, enabling the rapid amendment of treatment guidelines to improve patient outcomes and reduce the potential for the spread of drug-resistant parasites. A strong case-based surveillance system, integration with other health system processes, supporting biomarker collection and molecular analyses, and cross-border collaboration may maximize the potential of iDES in countries moving towards elimination.

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Progress and challenges of integrated drug efficacy surveillance for uncomplicated malaria in Thailand

Malaria Journal ◽

10.1186/s12936-021-03791-2 ◽

2021 ◽

Vol 20 (1) ◽

Author(s):

Prayuth Sudathip ◽

Aungkana Saejeng ◽

Nardlada Khantikul ◽

Thannikar Thongrad ◽

Suravadee Kitchakarn ◽

...

Keyword(s):

Plasmodium Falciparum ◽

System Integration ◽

Treatment Guidelines ◽

Drug Efficacy ◽

Fiscal Year ◽

Efficacy Rate ◽

First Line ◽

First Line Therapy ◽

Line Therapy ◽

Kaplan Meier

Abstract Background Integrated drug efficacy surveillance (iDES) was formally introduced nationally across Thailand in fiscal year 2018 (FY2018), building on a history of drug efficacy monitoring and interventions. According to the National Malaria Elimination Strategy for Thailand 2017–2026, diagnosis is microscopically confirmed, treatment is prescribed, and patients are followed up four times to ensure cure. Methods Routine patient data were extracted from the malaria information system for FY2018–FY2020. Treatment failure of first-line therapy was defined as confirmed parasite reappearance within 42 days for Plasmodium falciparum and 28 days for Plasmodium vivax. The primary outcome was the crude drug efficacy rate, estimated using Kaplan–Meier methods, at day 42 for P. falciparum treated with dihydroartemisinin–piperaquine plus primaquine, and day 28 for P. vivax treated with chloroquine plus primaquine; day 60 and day 90 efficacy were secondary outcomes for P. vivax. Results The proportion of patients with outcomes recorded at day 42 for P. falciparum malaria and at day 28 for P. vivax malaria has been increasing, with FY2020 follow-up rates of 61.5% and 57.2%, respectively. For P. falciparum malaria, day 42 efficacy in FY2018 was 92.4% (n = 249), in FY2019 93.3% (n = 379), and in FY2020 98.0% (n = 167). Plasmodium falciparum recurrences occurred disproportionally in Sisaket Province, with day 42 efficacy rates of 75.9% in FY2018 (n = 59) and 49.4% in FY2019 (n = 49), leading to an update in first-line therapy to pyronaridine–artesunate at the provincial level, rolled out in FY2020. For P. vivax malaria, day 28 efficacy (chloroquine efficacy) was 98.5% in FY2018 (n = 2048), 99.1% in FY2019 (n = 2206), and 99.9% in FY2020 (n = 2448), and day 90 efficacy (primaquine efficacy) was 94.8%, 96.3%, and 97.1%, respectively. Conclusions In Thailand, iDES provided operationally relevant data on drug efficacy, enabling the rapid amendment of treatment guidelines to improve patient outcomes and reduce the potential for the spread of drug-resistant parasites. A strong case-based surveillance system, integration with other health system processes, supporting biomarker collection and molecular analyses, and cross-border collaboration may maximize the potential of iDES in countries moving towards elimination.

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Rehabilitation approaches in cervical dystonia

Neurology neuropsychiatry Psychosomatics ◽

10.14412/2074-2711-2021-4-103-108 ◽

2021 ◽

Vol 13 (4) ◽

pp. 103-108

Author(s):

Z. A. Zalyalova ◽

E. R. Iusupova

Keyword(s):

Cervical Dystonia ◽

Treatment Guidelines ◽

First Line ◽

Rehabilitation Programs ◽

First Line Therapy ◽

Line Therapy ◽

Different Types ◽

Sensorimotor Mechanisms ◽

Gait Disturbances

Cervical dystonia (CD) is a form of focal muscular dystonia. The pathophysiology of CD includes central and peripheral sensorimotor mechanisms that lead to a pathological posture, imbalance, gait disturbances, and pain. Current CD treatment guidelines include botulinum toxin (BT) injections as first-line therapy. It has been established that a combination of BT injections and rehabilitation programs can reduce the disease severity, disability, and pain, improve the quality of life, and increase the duration and intensity of the BT. Even though different opinions exist on rehabilitation standards in patients with CD, several strategies are distinguished for its different types. Currently, complex kinesiotherapy for CD is being introduced, proposed by the French specialist J.P. Bleton and based on sensorimotor retraining. Other rehabilitation methods include biofeedback, transcutaneous electrical neurostimulation, and proprioceptive rehabilitation. Each of these methods has its own pathophysiological rationale in CD.

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