Project description:Overall, around 40% of patients with diffuse large B-cell lymphoma (DLBCL) have refractory disease or relapse after the first line of treatment. Until relatively recently, the prognosis of patients with relapsed or refractory DLBCL was very poor and treatment options were very limited. In recent years, several novel therapies have been approved that provide more effective options than conventional chemotherapy and that have manageable toxicity profiles. CAR-T cell therapy has become the new standard treatment for patients with refractory or early relapsed DLBCL, based on the positive results of the phase 3 ZUMA-7 and TRANSFORM clinical trials. This review addresses the role of CAR-T therapy and autologous stem cell transplantation in the treatment of these patients and other approved options for patients who are not candidates for transplant, such as the combinations of polatuzumab vedotin with bendamustine and rituximab, and tafasitamab with lenalidomide.
Project description:Systemic immunoglobulin light chain (AL) amyloidosis is a disorder characterized by the production of clonal serum free light chains that misfold, aggregate, and deposit in vital organs. Treatment of this disease is typically targeted at the abnormal plasma cell clone in the bone marrow which is the source of the amyloidogenic light chain. First-line therapies in this disease are well established, but in the relapsed or refractory setting, there are many treatment options, including immunomodulatory agents, proteasome inhibitors, alkylating agents, and monoclonal antibodies. Decisions regarding treatment choice should be made by a multidisciplinary team with consideration of the patient's functional status, disease stage, degree of organ dysfunction, and potential treatment toxicities. Herein we review the current treatment options available for patients with relapsed or refractory AL amyloidosis.
Project description:Despite advances in monitoring and treatment, cytomegalovirus (CMV) infections remain one of the most common complications after solid organ transplantation (SOT). CMV infection may fail to respond to standard first- and second-line antiviral therapies with or without the presence of antiviral resistance to these therapies. This failure to respond after 14 days of appropriate treatment is referred to as "resistant/refractory CMV." Limited data on refractory CMV without antiviral resistance are available. Reported rates of resistant CMV are up to 18% in SOT recipients treated for CMV. Therapeutic options for treating these infections are limited due to the toxicity of the agent used or transplant-related complications. This is often the challenge with conventional agents such as ganciclovir, foscarnet and cidofovir. Recent introduction of new CMV agents including maribavir and letermovir as well as the use of adoptive T cell therapy may improve the outcome of these difficult-to-treat infections in SOT recipients. In this expert review, we focus on new treatment options for resistant/refractory CMV infection and disease in SOT recipients, with an emphasis on maribavir, letermovir, and adoptive T cell therapy.
Project description:Mantle cell lymphoma (MCL) is an uncommon subtype of non-Hodgkin lymphoma in which immunochemotherapy, with or without high-dose therapy, and autologous stem cell transplantation remain standard frontline therapies. Despite their clear efficacy, patients inevitably relapse and require subsequent therapy. In this review, we discuss the key therapeutic approaches in the management of relapsed MCL, covering in depth the data supporting the use of covalent Bruton tyrosine kinase (BTK) inhibitors at first or subsequent relapse. We describe the outcomes of patients progressing through BTK inhibitors and discuss the mechanisms of covalent BTKi resistance and treatment options after covalent treatment with BTKi. Options in this setting may depend on treatment availability, patient's and physician's preference, and the patient's age and comorbidity status. We discuss the rapid recent development of anti-CD19 chimeric antigen receptor T-cell therapy, as well as the utility of allogenic stem cell transplantation and novel therapies, such as noncovalent, reversible BTK inhibitors; ROR1 antibody drug conjugates; and bispecific antibodies.
Project description:The use of modern therapies such as thalidomide, bortezomib and lenalidomide coupled with upfront high-dose therapy and autologous stem cell transplant (ASCT) has resulted in improved survival in patients with newly diagnosed multiple myeloma (MM). However, patients with relapsed/refractory multiple myeloma (RRMM) often have poorer clinical outcomes and might benefit from novel therapeutic strategies. Emerging therapies, such as deacetylase inhibitors, monoclonal antibodies and new proteasome inhibitors, appear promising and may change the therapeutic landscape in RRMM. A limited number of studies has shown a benefit with salvage ASCT in patients with RRMM, although there remains ongoing debate about its timing and effectiveness. Improvement in transplant outcomes has re-ignited a debate on the timing and possible role for salvage ASCT and allogeneic stem cell transplant in RRMM. As the treatment options for management of patients with RRMM become increasingly complex, physicians must consider both disease- and patient-related factors in choosing the appropriate therapeutic approach, with the goal of improving efficacy while minimizing toxicity.
Project description:BackgroundThe refractory/relapsed multiple myeloma (RRMM) remains a big clinical challenge, due to its biological and clinical complexity. Leading hematologists have performed many randomized controlled trials (RCTs) worldwide, and their findings were summarized in a recently published network meta-analysis (NMA) but with certain limitations.Materials and methodsWe performed an updated NMA of RCTs related to RRMM treatment, focusing on efficacy measures including the nonresponse rate (NRR), time to progression (TTP), progression-free survival (PFS), and overall survival (OS). The PubMed database was searched. We extended the literature search strategy of a previous NMA to June 30, 2017 and included additional primary RCTs. The surface under the cumulative ranking curve (SUCRA) was calculated to rank the regimens. A weighted-average method was used to rank the regimens by summarizing SUCRAs across different outcome measures.ResultsFinally, a total of 24 RCTs were included in this updated NMA. According to the result, the combination of daratumumab, lenalidomide, and dexamethasone showed better efficacy than other regimens in terms of NRR, TTP, and PFS (NRR: odds ratio [OR] =0.046, 95% credible interval [CrI] =[0.024, 0.085]; TTP: hazard ratio [HR] =0.14, 95% CrI =[0.092, 0.2]; PFS: HR =0.12, 95% CrI =[0.077, 0.18], compared with dexamethasone singlet). The combination of ixazomib, lenalidomide, and dexamethasone showed better efficacy than other regimens in terms of OS (HR =0.30, 95% CrI =[0.17, 0.54], compared with dexamethasone). The combination of daratumumab, lenalidomide, and dexamethasone ranked first in terms of overall efficacy (weighted average of SUCRAs =0.920).ConclusionThe combination of daratumumab, lenalidomide, and dexamethasone may currently be the most effective regimen in the population of RRMM patients. Triplet regimens containing daratumumab, ixazomib, carfilzomib, or elotumumab plus lenalidomide and dexamethasone can be recommended as first-line therapies for RRMM patients.
Project description:Epithelial ovarian cancer (EOC) is a significant cause of cancer-related mortality in women. Despite advances in diagnosis and treatment, EOC remains a challenging disease to manage, and the 5-year survival rate is still poor. The role of hormone receptors (HRs) in EOC carcinogenesis and prognosis has been actively explored; however, the role of hormone therapy (HT) in the treatment of these tumors is not well established. Most available data on HT mainly come from retrospective series and small early clinical trials. Several of these studies suggest that HT may have a role in adjuvant, maintenance therapy, or in the case of recurrent disease, especially for some subtypes of EOC (e.g., low-grade serous EOC). Furthermore, HT has recently been combined with targeted therapies, but most studies evaluating these combinations are still ongoing. The main aim of this review is to provide an overview of the progress made in the last decade to characterize the biological and prognostic role of HRs for EOC and the developments in their therapeutic targeting through HT.
Project description:Indications for intervention in hemodynamically relevant carotid artery stenosis (carotid endarterectomy or stenting) are primarily based on a degree of stenosis and symptomatology. To date the plaque vulnerability is rarely taken into account in clinical decision making although development of molecular imaging allows a better understanding of plaque biology and provides new techniques detecting potentially vulnerable plaque at risk. A significant number of reports describing the mechanisms of unstable plaque formation suggest that it is a multifactorial process. Inflammation, lipid accumulation, apoptosis, proteolysis, the thrombotic process and angiogenesis are among the main factors of carotid plaque destabilization. Although inflammation is a key process in development of plaque vulnerability, the hemostasis and neoangiogenesis should be regarded as equally important. Only a small group of asymptomatic patients may benefit from the invasive treatment and it remains a challenge to determine whether initially asymptomatic carotid plaque become unstable or vulnerable. Currently, the main task of research on atherosclerotic lesion imaging is focused on functional state of the plaque. The presence of one or more features such as stenosis progression, large plaque area, large juxta-luminal black area, plaque echolucency, intra-plaque hemorrhage, impaired cerebral vascular reserve and spontaneous embolization may indicate patients at higher risk for stroke suitable for revascularization. Treatment of carotid stenosis as one of the manifestations of generalized atherosclerosis requires a broad approach. Nowadays pharmacological treatment options for the atherosclerotic process are largely aimed at stimulating the plaque stabilization, but in symptomatic patients and selected asymptomatic patients, carotid plaque should be removed as a potential source of embolism.
Project description:Targeted radiopharmaceuticals for therapeutic use deliver radionuclides directly to tumor anywhere in the body, and therefore, have renewed interest for clinical development in women with disseminated chemorefractory ovarian cancers. About two in every five women with advanced stage ovarian cancer outlive their disease after the first treatment phase, with the rest rendered incurable due to the chemorefractory nature of their disease. The National Cancer Institute (NCI) Cancer Therapy Evaluation Program conducted 67 phase I or phase Ib trials among women with relapsed or refractory ovarian cancer between 1989 and 2017 in an effort to uncover tolerable and effective drug combinations intended to increase survival rates. None of these early clinical development phase trials involved radiopharmaceuticals. Here, the NCI provides its perspective on targeted radiopharmaceutical conjugates alone or in combination with its experimental therapeutics portfolio for women with relapsed or refractory ovarian cancer. An infrastructure build for Federal radiopharmaceutical medical monitoring and adverse event reporting has begun.
Project description:The medical and surgical treatment strategies for women with epithelial ovarian cancer continue to evolve. In the past several years, there has been significant progress backed by landmark clinical trials. Although primary epithelial ovarian cancer is still treated with a combination of surgery and systemic therapy, more complex surgical procedures and novel therapeutics have emerged as standard of care. Cytotoxic chemotherapy and maximal surgical effort remain mainstays, but targeted therapies are becoming more widespread and new data have called into question the role of surgery for women with recurrent disease. Poly ADP-ribose polymerase inhibitors have improved progression-free survival outcomes in both the frontline and recurrent settings, and their use has become increasingly widespread. The recent creation of treatment categories based on genetic changes reinforces the recommendation that all women with epithelial ovarian cancer have germline genetic testing, and new biomarker-driven drug approvals indicate that women may benefit from somatic molecular testing as well. To continue to identify novel strategies, however, enrollment on clinical trials remains of the utmost importance. With the evolving data on surgical approaches, targeted therapies such as antiangiogenics and poly ADP-ribose polymerase inhibitors, and the new therapeutic agents and combinations in development, we hope that advanced epithelial ovarian cancer will eventually transition from an almost universally fatal disease to one that can increasingly be cured.