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Presenter : Aaron T. Gerds

Myelofibrosis (MF) is a symptom-forward disease, and its treatment focuses on alleviating those symptoms, as well as improving survival. An initial disease risk assessment is critical for deciding on a course of therapy (and a number of models can be used depending on the available patient information), and anemia can be considered a special case within the treatment algorithms for MF. JAK-STAT inhibition is currently the cornerstone of treatment for MF, but these inhibitors are not perfect. Future research will focus on the microenvironment in reversing fibrosis, immunotherapies, proliferative signaling pathways, epigenetic regulators, and stem cells.

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Presenter : Eric D. Hsi

The many different subtypes of non-Hodgkin lymphoma can be distinguished by histopathology, immunophenotype, and underlying genetic abnormalities. Molecular testing is routinely used by pathologists for diagnosis and prognosis, and to aid in guiding therapy selection (targeted or nontargeted). The different tools and techniques used for molecular testing are based on abnormality type and tissue available.

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Presenter : Steven M. Horwitz

Peripheral T-cell lymphomas–not otherwise specified (PTCL-NOS) is a broad category of biologically and clinically heterogeneous diseases, which likely does not have a single treatment paradigm. Understanding of subtype-specific approaches is leading to more individualized therapy. There are also therapeutic vulnerabilities to target, such as CD30, JAK/STAT pathway, and epigenetic modifiers, that may cross different histologic subtypes. As new therapies evolve, however, it is important to understand in which situations current standard treatments work, because some of these treatments, such as combination chemotherapy, are potentially curative for a subset of patients. For certain populations, adding to these chemotherapy backbones will produce the best results. For other populations, entirely new approaches may be appropriate. Future treatment advances will, in part, be made by enriching populations based on their likelihood of response to specific therapies and utilizing biomarker-driven or biomarker-informed strategies.

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Presenter : Andrew D. Zelenetz

CAR T cells have demonstrated activity in relapsed/refractory non-Hodgkin lymphoma, including diffuse large B-cell lymphoma (DLBCL), indolent non-Hodgkin lymphoma, and mantle cell lymphoma. For patients with chemorefractory disease, CAR T cells can provide a durable complete response in a portion of patients, which represents a major advance in the field. For patients with chemosensitive disease, however, additional data are needed to determine whether CAR T cells are preferable to conventional approaches. Studies in DLBCL have shown that patients experiencing a PET-positive partial response after second-line chemotherapy have long-term outcomes after high-dose therapy and autologous stem cell rescue that are similar to CAR T-cell therapy, with decreased toxicity and cost. Alternative third-line options such as tafasitamab/lenalidomide and bispecific antibodies may also have a role for patients with chemorefractory disease.

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Presenter : Natalie S. Callander

Smoldering multiple myeloma represents approximately 10% to 15% of all myeloma cases, but more thorough evaluation may decrease that number in the future. Risk stratification is important in this patient population to avoid overtreatment or undertreatment. Patients with low-risk disease can be observed without treatment, but those at higher-risk should be enrolled on clinical trials. If a clinical trial is not an option in these patients, a time-limited intervention with lenalidomide ± dexamethasone can be considered.

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Presenter : William G. Wierda

Progress in the treatment of chronic lymphocytic leukemia/small lymphocytic lymphoma has led to a renewed focus on minimal residual disease as a treatment endpoint, particularly in assessing survival outcomes with combination therapies. B-cell receptor signaling pathway inhibitor monotherapy is associated with low rates of undetectable minimal residual disease, and continued treatment is still required; however, BCL-2 inhibitor therapy with venetoclax is associated with high rates of undetectable minimal residual disease, as are new combinations with BCL-2 inhibitors. Early research indicates that BCL-2 inhibitors may be an effective treatment option for disease that is refractory to Bruton’s tyrosine kinase (BTK) inhibitor therapy.

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Luciano J. Costa and Saad Z. Usmani

Multiple myeloma is a very heterogeneous disease. Despite advances in diagnostics and therapeutics, a subset of patients still experiences abbreviated responses to therapy, frequent relapses, and short survival and is considered to have high-risk multiple myeloma (HRMM). Stage III diagnosis according to the International Staging System; the presence of del(17p), t(4;14), or t(14;16) by fluorescence in situ hybridization; certain gene expression patterns; high serum lactic dehydrogenase level; and the presence of extramedullary disease at diagnosis are all considered indicators of HRMM. More recent evidence shows that patients who experience response to therapy but with a high burden of measurable residual disease or persistence of abnormal FDG uptake on PET/CT scan after initial therapy also have unfavorable outcomes, shaping the concept of dynamic risk assessment. Triplet therapy with proteasome inhibitors, immunomodulatory agents, and corticosteroids and autologous hematopoietic cell transplantation remain the pillars of HRMM therapy. Recent evidence indicates a benefit of immunotherapy with anti-CD38 monoclonal antibodies in HRMM. Future trials will inform the impact of novel immunotherapeutic approaches, including T-cell engagers, CAR T cells, and nonimmunotherapeutic approaches in HRMM. Those agents are likely to be deployed early in the disease course in the setting of risk- and response-adapted trials.

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Timothy M. Schmidt and Natalie S. Callander

The presence of monoclonal proteins is common, with a prevalence in the United States around 5% that increases with age. Although most patients are asymptomatic, most cases are caused by a clonal plasma cell disorder. Monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM) are asymptomatic precursor conditions with variable risk of progression to multiple myeloma. In recent years, significant progress has been made to better understand the factors that lead to the development of symptoms and progression to myeloma. This review summarizes the current diagnosis treatment guidelines for MGUS and SMM and highlights recent advances that underscore a shifting paradigm in the evaluation and management of plasma cell precursor conditions.