Ipertiroidismo e tiroidite autoimmune in età evolutiva

Hyperthyroidism is a rare clinical entity in paediatric age. In most cases the etiology is autoimmune and goiter represents the typical presentation. Ophthalmopathy is rare and can precede the diagnosis of autoimmune hyperthyroidism. Thyrotoxicosis caused by the hyperthyroid phase of Hashimoto’s thyroiditis must be carefully distinguished from Graves’ disease (GD), since the first condition has a better prognosis for spontaneous remission. Three treatment options are currently available for the management of paediatric GD. First-line therapy is antithyroid drugs, while thyroidectomy and radioiodine are considered on relapse. A lower remission rate and a higher risk of adverse events are observed after the first course of methimazole in childhood with respect to adulthood. Children and adolescents may require a prolonged antithyroid treatment, but an overall consensus regarding the optimal regimen is lacking.

Chemo-Free Treatments in Relapsed and/or Refractory Follicular Lymphoma: A Network Meta-Analysis

Review question / Objective: FL is the most common indolent B cell lymphoma worldwide and patients with FL always have long term survival. However, advanced FL remains incurable and there is no universal agreement on optimal regimen to manage relapsed FL. Condition being studied: The efficacy of chemo-free regimens, including CD20 antibodies and targeted agents, in relapsed and/or refractory Follicular lymphoma. Information sources: We used the MEDLINE, Embase, and Cochrane Library databases to search the RCTs met our selection criteria. We also searched clinicalTrials.gov and the international clinical trial registry platform for completed and ongoing trials. In addition, we searched abstracts that published on American Society of Hematology (ASH), The European Hematology Association (EHA) or American Society of Clinical Oncology (ASCO) meetings.

Antiretroviral Therapy in Children and Adolescents: A Look Into Modern Single Tablet Regimens

Single tablet regimens (STRs) have simplified antiretroviral therapy (ART) over the years in the adult human immunodeficiency virus (HIV) population. However, there is still a prevalent need to simplify regimens in children and adolescents living with HIV. Finding the optimal regimen requires a multi-factorial approach due to their complex pharmacokinetic profiles throughout childhood and the challenges and limitations of medication non-adherence in the pediatric population. These challenges include pill size, available formulations, palatability, and caregiver health literacy, which can all affect the proper administration of medications. The complexity of this population implies the importance of customizing everyone's antiretroviral regimen so that the patient and family can successfully adhere to the therapy. The current recommendations for ART in the adult and pediatric populations are similar, yet the use of STRs are limited. The goal of this review was to assess current data on available STRs and determine their utility as ART in the pediatric population.

A Phase 2/3 Randomized, Placebo-Controlled, Open-Label, Multi-Center Trial of Lenzilumab to Improve the Safety and Efficacy of CAR-T Cell Therapy in Adults with Relapsed or Refractory Large B-Cell Lymphoma (The SHIELD Study)

Background: Diffuse large B-cell lymphoma (DLBCL) is the most common aggressive sub-type of non-Hodgkin's lymphoma(Liu, et al. Am J Hematol 2019). All three approved CD19-directed CAR-T therapies (axicabtagene ciloleucel, tisagenlecleucel, lisocabtagene maraleucel) are associated with toxicities, including cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) that can be severe, resulting in non-relapse mortality, ICU admission, and significant non-drug related health resource utilization which represent barriers to access and adoption (Nabhan, et al. J Clin. Pathway 2017). Studies have shown that early elevation of granulocyte-macrophage colony-stimulating factor (GM-CSF) levels 1-day post CAR-T infusion correlates with severe ICANS (Rossi, et al. EMA Workshop 2016), which is a negative prognostic factor for overall survival (Karschnia, et al. Blood 2019). It has been proposed that upon contact with the tumor, CAR-Ts produce GM-CSF, which serves as a communication conduit between the specific immune response of CAR-T and the off-target inflammatory cascade produced by myeloid lineage cells, causing myeloid cells to expand and promote the production of other downstream proinflammatory chemokines (MCP-1, IL-8, IP-10), cytokines (IL-1, IL-6), and other markers of systemic inflammation (CRP, Ferritin) (Sterner, et al. Blood 2019). Moreover, IL-6 is predominately released by tumor cells in a contact-independent manner (Barrett et al. Blood 2016), which helps explain why the prophylactic administration of tocilizumab is not effective in reducing the overall incidence of CRS or ICANS, as this cytokine is downstream in the inflammatory cascade. Further, the prophylactic use of tocilizumab has been shown to increase the incidence of all-grades and grade >3 ICANS (Locke, et al. Blood 2017). Lenzilumab is a novel Humaneered ® monoclonal antibody that neutralizes GM-CSF and has demonstrated potential to reduce the hyper-immune mediated cytokine storm induced by SARS-CoV-2 infection and significantly improve the likelihood of survival without ventilation in hospitalized COVID-19 patients, as reported in the LIVE-AIR phase 3 study (Temesgen, et al. medRxiv 2021). Methods: Eligible patients are adults (≥ 18 y) with relapsed or refractory DLBCL or are chemorefractory. Prior therapy must have included an anti-CD20 monoclonal antibody and an anthracycline-containing regimen. Patients will undergo leukapheresis and may receive optional corticosteroid bridging therapy. Patients will then receive lymphodepleting chemotherapy on Days ‒3 to ‒5 followed by infusion of lenzilumab on Day 0, 6-hrs prior to CAR-T infusion. Approximately 40 accredited sites across the U.S. certified to administer the three commercially available CAR-Ts have been engaged to participate in this 2-part study. In Part 1, all patients will receive lenzilumab 1800mg via a single 2-hour infusion prior to CAR-T administration. The objective of Part 1 is to evaluate the optimal regimen and assess whether a second dose of lenzilumab post-CAR-T infusion is required. A translational assessment of GM-CSF axis suppression, levels of CAR-T cells in blood, other inflammatory markers and lenzilumab PK/PD will be evaluated, along with the incidence and severity of CRS and ICANS, objective response rates (ORR) and rates of complete response (CR) by Day 28 to select the optimal regimen to carry forward into Part 2. The objective of Part 2 is to confirm whether lenzilumab can improve the toxicity and tolerance of CAR-T while maintaining or improving efficacy and durability of response. Up to 250 patients will be randomized 1:1 to receive lenzilumab or placebo with CAR-T per standard of care. The primary endpoint of the study is incidence of grade >2 CRS and/or ICANS by Day 28, with a key secondary endpoint of CR at 6-months in patients without grade ≥ 2 CRS and/or ICANS at Day 28 (Toxicity-free CR). This design and sample size yields 90% power to detect a 50% reduction in the primary outcome measure. Secondary endpoints include incidence of all grades and grade >3 CRS and/or ICANS, respectively; ORR and CR at 1, 3, 6, 12 months; durability of CR; progression-free survival, overall survival and health related quality of life using validated patient reported outcome measures. In addition, the study will explore the CRS and ICANS grading criteria that have been utilized with each of the approved CAR-Ts. Disclosures Kenderian: Humanigen, Inc.: Consultancy, Honoraria, Research Funding. Durrant: Humanigen, Inc.: Current Employment, Current equity holder in publicly-traded company, Divested equity in a private or publicly-traded company in the past 24 months. Chappell: Humanigen Inc.: Current Employment, Current equity holder in publicly-traded company, Divested equity in a private or publicly-traded company in the past 24 months. Ahmed: Humanigen Inc.: Current Employment, Current equity holder in publicly-traded company. Kilcoyne: Humanigen, Inc.: Current Employment, Current equity holder in publicly-traded company.

Management of Multiple Myeloma in Older Patients

Multiple myeloma is a condition that affects predominantly the older population. There are now various approved chemotherapy regimens as a result of advances in treatment. Choosing the optimal regimen for older patients with myeloma remains a challenge because of frailty and a lack of head-to-head comparisons between backbone regimens. The purpose of this literature review is to summarise the recent literature on frailty assessment, disease biology, and treatment efficacy in the frontline and relapsed settings to aid the decision-making process.

Clozapine rechallenge following neutropenia using granulocyte colony-stimulating factor: A Quebec case series

Background: Clozapine has a unique efficacy profile among individuals suffering from treatment-resistant schizophrenia, but is associated with hematological side effects. The use of granulocyte colony-stimulating factors (G-CSF) to allow clozapine continuation or rechallenge has emerged as a promising option, but evidence is still scarce. Aim: To describe the largest case series so far published regarding this practice. Method: A national clozapine hematological monitoring database was consulted to identify all patients who had had neutrophil count <1.5 × 109/L since 2004 in Quebec and was cross-referenced with hospital pharmacy software to identify patients who had received at least one dose of G-CSF, such as filgrastim, while being exposed to clozapine. All data were collected retrospectively, using patients’ medical files, from January to July 2019. Results: Using G-CSF, three out of eight patients could maintain clozapine despite neutropenia episodes that otherwise would have required treatment discontinuation. The only side effect reported was mild short-lived back pain, over a mean 3-year follow-up period. In all but one case, filgrastim was used on an “as-needed” basis at doses of 300 mcg administered subcutaneously. Conclusion: These results suggest that the “as-needed” use of G-CSF is well-tolerated and may allow clozapine rechallenge in some well-selected patients, adding to the paucity of data regarding long-term safety and efficacy of this strategy. More research may help to better define potential candidates and optimal regimen of such practice.

The Optimal Adjuvant Strategy of Aidi Injection With Gemcitabine and Cisplatin in Advanced Non–small Cell Lung Cancer: A Meta-analysis of 70 Randomized Controlled Trials

Introduction: Aidi injection (Aidi) is composed of cantharidin, astragaloside, ginsenoside, and elentheroside E. As an important adjuvant therapy, Aidi in combination with gemcitabine and cisplatin (GP) is often used in the treatment of non-small cell lung cancer (NSCLC).Objectives: We performed a new evaluation to demonstrate the clinical efficacy and safety of the Aidi and GP combination and further explored an optimal strategy for achieving an ideal response and safety level in advanced NSCLC.Methodology: We collected all the related trials from Chinese and English-language databases, analyzed their methodological bias risk using the Cochrane evaluation Handbook for Systematic Reviews of Interventions Version 5.1.0, extracted all the data using a predefined data extraction form, pooled the data using a series of meta-analyses, and finally summarized the quality of evidence using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach.Results: We included 70 trials with 5,509 patients. Compared with GP alone, the Aidi and GP combination showed a significant improvement in the objective response rate (ORR) [1.82 (1.62–2.04)], disease control rate (DCR) [2.29 (1.97–2.67)], and quality of life (QOL) [3.03 (2.55–3.60)] and a low incidence of hematotoxicity and gastrointestinal and hepatorenal toxicity. Aidi might be more suitable for patients who are first-treated, elderly, or patients with a Karnofsky Performance Status (KPS) score ≥ 60 or anticipated survival time (AST) ≥3 months. An Aidi (50 ml/day, 7–14 days/cycle for one to two cycles), gemcitabine (1000 mg/m2), and cisplatin (20–30 mg/m2, 40–50 mg/m2, or 60–80 mg/m2) might be an optimal regimen for realizing an ideal response and safety level. Most results were robust and of moderate quality.Conclusion: Current evidence indicates that Aidi's value in adjuvant chemotherapy may be broad-spectrum, not just for some regimens. The Aidi and GP combination may show a good short-term response, antitumor immunity, and safety level in patients with NSCLC. Aidi (50 ml/day, 7–14 days/cycle for one and two cycles) with GEM (1000 mg/m2) and DDP (20–30 mg/m2 or 40–50 mg/m2) may be an optimal regimen for realizing an ideal goal in patients who are first-treatment, elderly, or have a KPS score ≥ 60 or AST≥3 months.

ENGOT-ov60/GOG3052/RAMP 201: A phase 2 study of VS-6766 (dual RAF/MEK inhibitor) alone and in combination with defactinib (FAK inhibitor) in recurrent low-grade serous ovarian cancer (LGSOC).

TPS5603 Background: VS-6766 is a unique small molecule inhibitor that blocks MEK kinase activity and RAF phosphorylation of MEK. This mechanism of blockade has been shown to limit compensatory MEK activation, thereby potentially enhancing efficacy of MEK inhibition. Defactinib, (VS-6063), an orally active small molecule, is a potent adenosine 5'- triphosphate (ATP) competitive, reversible inhibitor of focal adhesion kinase (FAK). Defactinib has shown synergistic activity with BRAF and MEK inhibitors in both in vitro and in vivo solid tumor models. Prior molecularly unselected studies with single agent MEK inhibitors have shown response rates up to 26% in recurrent LGSOC. A third of patients with recurrent LGSOC harbor somatic KRAS mutations. FAK inhibition has been shown to induce tumor regression when combined with RAF, MEK or RAF/MEK inhibitors in in vivo models of KRAS mutant ovarian cancer. The combination of VS-6766 and defactinib is currently being evaluated in the ongoing Investigator Sponsored FRAME study (NCT03875820). In this proof of concept study, durable objective responses have been reported in recurrent LGSOC patients, particularly those with KRAS mutations including patients who have had a prior MEK inhibitor (Banerji et al AACR 2020). Based on preclinical studies demonstrating efficacy of both VS-6766 and the VS-6766/defactinib combination and preliminary results of the FRAME study, the phase II ENGOT-ov60/GOG3052 has been developed in recurrent LGSOC. Methods: This is a Phase II, adaptive, two-part, multicenter, parallel cohort, randomized, open label study designed to evaluate the efficacy and safety of VS-6766 versus VS-6766 in combination with defactinib (NCT04625270). The study will be conducted in two parts. Part A will determine the optimal regimen based on confirmed overall response rate (independent radiology review) in KRAS-mutated LGSOC. Part B will determine the efficacy of the optimal regimen identified in Part A in KRAS-mutated and KRAS wild-type LGSOC. The minimum expected enrollment is 52 subjects with KRAS-mutated tumors (32 subjects in Part A and 20 in Part B) and 36 with KRAS wild-type tumors in Part B. Patients will be randomized to receive VS-6766 (4.0 mg PO, twice weekly 3 weeks on, 1 week off) or VS6766 with defactinib (VS-6766 3.2 mg PO, twice weekly + defactinib 200 mg PO BID 3 weeks on, 1 week off) till progression. Key inclusion criteria include histologically confirmed LGSOC, presence of KRAS mutation (Part A), prior systemic therapy for metastatic disease and up to 1 prior line of MEK/RAF inhibitor therapy permitted. This international study is open to enrollment. Clinical trial information: NCT04625270.