Copanlisib for the Treatment of Malignant Lymphoma: Clinical Experience and Future Perspectives.

Dysregulation of phosphatidylinositol 3-kinase (PI3K)/protein kinase B/mammalian target of rapamycin signaling is common in both indolent and aggressive forms of malignant lymphoma, for which several targeted therapies have been developed. Copanlisib is a highly selective and potent intravenous pan-class I PI3K inhibitor that has demonstrated durable objective responses and a manageable safety profile in heavily pre-treated patients with indolent lymphomas. As a result, copanlisib monotherapy received accelerated approval from the US Food and Drug Administration for the treatment of adults with relapsed follicular lymphoma who have received at least two systemic therapies, and breakthrough designation for patients with pre-treated relapsed or refractory marginal zone lymphoma. Hyperglycemia and hypertension are among the most frequently reported adverse events with copanlisib monotherapy, and are infusion-related, transient, and manageable with standard therapies. Mild diarrhea is also a common adverse event with copanlisib monotherapy; there is no evidence of worsening severity of diarrhea, or serious gastrointestinal toxicities such as colitis or severe liver enzyme elevations, which have been reported with orally administered PI3K inhibitors. The intravenous route of administration and intermittent dosing schedule of copanlisib may support a favorable tolerability profile over continually administered oral alternatives. Ongoing studies of copanlisib in combination with rituximab and standard-of-care chemotherapy in patients with relapsed indolent lymphoma have the potential to support the use of copanlisib in the second-line setting, providing a much-needed additional therapeutic option in this underserved patient population

Evaluating the impact of eligibility criteria in first-line clinical trials for follicular lymphoma: A MER/LEO cohort analysis

Cancer clinical trial eligibility criteria may create patient populations studied in trials that do not reflect the patient populations treated in the real-world setting. Follicular lymphoma (FL) is an indolent lymphoma with heterogeneous presentations across a broad range of individuals, resulting in many acceptable management strategies. We evaluated how first-line clinical trial eligibility criteria impacted the demographic makeup and outcomes of patients with FL for whom systemic therapy might be considered. We compared the characteristics of 196 patients with FL from a single institution to eligibility criteria from 10 first-line FL trials on clinicaltrials.gov. Next, we tabulated eligibility criteria from 24 first-line FL protocols and evaluated their impact on 1198 patients with FL with stages II to IV disease from the prospective Molecular Epidemiology Resource (MER) and Lymphoma Epidemiology of Outcomes (LEO) cohort studies. We found that 39.8% and 52.7% of patients with FL might be excluded from clinical trials based on eligibility criteria derived from clinicaltrials.gov and protocol documents, respectively. Patients excluded because of renal function, prior malignancy, and self-reported serious health conditions tended to be older. Expanding stage requirement from III-IV to II-IV, and platelet requirement from ≥150 000 to ≥75 000 increased population size by 21% and 8%, respectively, in MER and by 16% and 13%, respectively, in LEO, without impacting patient demographics or outcomes. These data suggest that management of older individuals with FL may not be fully informed by recent clinical trials. Moreover, liberalizing stage and platelet criteria might expand the eligible population and allow for quicker trial accrual without impacting outcomes

An international multicenter retrospective analysis of patients with extranodal marginal zone lymphoma and histologically confirmed central nervous system and dural involvement

Marginal zone lymphoma of the central nervous system (CNS MZL) is rare. The clinical features, treatment, and prognosis are not well characterized. We performed a multicenter retrospective study of CNS MZL. Twenty-six patients were identified: half with primary and half with secondary CNS involvement. The median age was 59 years (range 26-78), 62% female and 79% with ECOG performance status ≤ 1. The most common disease site was the dura (50%). Treatment was determined by the treating physician and varied substantially. After a median follow up of 1.9 years, the estimated 2-year progression-free (PFS) and overall survival (OS) rates were 59% and 80%, respectively. Secondary CNS MZL was associated with 2-year OS of 58%. CNS MZL is rare, but relative to other forms of CNS lymphoma, outcomes appear favorable, particularly among the subset of patients with dural presentation and primary CNS presentation

Follicular Lymphoma: Recent and Emerging Therapies, Treatment Strategies, and Remaining Unmet Needs

Follicular lymphoma (FL) is a heterogeneous disease with varying prognosis owing to differences in clinical, laboratory, and disease parameters. Although generally considered incurable, prognosis for early- and advanced-stage disease has improved because of therapeutic advances, several of which have resulted from elucidation of the biologic and molecular basis of the disease. The choice of treatment for FL is highly dependent on patient and disease characteristics. Several tools are available for risk stratification, although limitations in their routine clinical use exist. For limited disease, treatment options include radiotherapy, rituximab monotherapy or combination regimens, and surveillance. Treatment of advanced disease is often determined by tumor burden, with surveillance or rituximab considered for low tumor burden and chemoimmunotherapy for high tumor burden disease. Treatment for relapsed or refractory disease is influenced by initial first-line therapy and the duration and quality of the response. Presently, there is no consensus for treatment of patients with early or multiply relapsed disease; however, numerous agents, combination regimens, and transplant options have demonstrated efficacy. Although the number of therapies available to treat FL has increased together with an improved understanding of the underlying biologic basis of disease, the best approach to select the most appropriate treatment strategy for an individual patient at a particular time continues to be elucidated. This review considers prognostication and the evolving treatment landscape of FL, including recent and emergent therapies as well as remaining unmet needs. Implications for Practice: In follicular lymphoma, a personalized approach to management based on disease biology, patient characteristics, and other factors continues to emerge. However, application of current management requires an understanding of the available therapeutic options for first-line treatment and knowledge of current development in therapies for previously untreated and for relapsed or refractory disease. Thus, this work reviews for clinicians the contemporary data in follicular lymphoma, from advances in characterizing disease biology to current treatments and emerging novel therapies

Subtype-Specific and Co-Occurring Genetic Alterations in B-cell Non-Hodgkin Lymphoma

B-cell non-Hodgkin lymphoma (B-NHL) encompasses multiple clinically and phenotypically distinct subtypes of malignancy with unique molecular etiologies. Common subtypes of B-NHL, such as diffuse large B-cell lymphoma, have been comprehensively interrogated at the genomic level, but rarer subtypes, such as mantle cell lymphoma, remain less extensively characterized. Furthermore, multiple B-NHL subtypes have thus far not been comprehensively compared using the same methodology to identify conserved or subtype-specific patterns of genomic alterations. Here, we employed a large targeted hybrid-capture sequencing approach encompassing 380 genes to interrogate the genomic landscapes of 685 B-NHL tumors at high depth, including diffuse large B-cell lymphoma, mantle cell lymphoma, follicular lymphoma, and Burkitt lymphoma. We identified conserved hallmarks of B-NHL that were deregulated in the majority of tumors from each subtype, including frequent genetic deregulation of the ubiquitin proteasome system. In addition, we identified subtype-specific patterns of genetic alterations, including clusters of co-occurring mutations and DNA copy number alterations. The cumulative burden of mutations within a single cluster were more discriminatory of B-NHL subtypes than individual mutations, implicating likely patterns of genetic cooperation that contribute to disease etiology. We therefore provide the first cross-sectional analysis of mutations and DNA copy number alterations across major B-NHL subtypes and a framework of co-occurring genetic alterations that deregulate genetic hallmarks and likely cooperate in lymphomagenesis

Exploring Risk Factors for Follicular Lymphoma

Follicular lymphoma (FL) is an indolent malignancy of germinal center B cells with varied incidence across racial groups and geographic regions. Improvements in the classification of non-Hodgkin lymphoma subtypes provide an opportunity to explore associations between environmental exposures and FL incidence. Our paper found that aspects of Western lifestyle including sedentary lifestyle, obesity, and diets high in meat and milk are associated with an increased risk of FL. Diets rich in fruits and vegetables, polyunsaturated fatty acids, vitamin D, and certain antioxidants are inversely associated with FL risk. A medical history of Sjogren's syndrome, influenza vaccination, and heart disease may be associated with FL incidence. Associations between FL and exposure to pesticides, industrial solvents, hair dyes, and alcohol/tobacco were inconsistent. Genetic risk factors include variants at the 6p21.32 region of the MHC II locus, polymorphisms of the DNA repair gene XRCC3, and UV exposure in individuals with certain polymorphisms of the vitamin D receptor. Increasing our understanding of risk factors for FL must involve integrating epidemiological studies of genetics and exposures to allow for the examination of risk factors and interactions between genes and environment

Comparing the Cost-Effectiveness of Rituximab Maintenance and Radioimmunotherapy Consolidation versus Observation Following First-Line Therapy in Patients with Follicular Lymphoma

AbstractBackgroundPhase 3 randomized trials have shown that maintenance rituximab (MR) therapy or radioimmunotherapy (RIT) consolidation following frontline therapy can improve progression-free survival for patients with follicular lymphoma (FL), but the cost-effectiveness of these approaches with respect to observation has not been examined using a common modeling framework.ObjectivesTo evaluate and compare the economic impact of MR and RIT consolidation versus observation, respectively, following the first-line induction therapy for patients with advanced-stage FL.MethodsWe developed Markov models to estimate patients’ lifetime costs, quality-adjusted life-years (QALYs), and life-years (LYs) after MR, RIT, and observation following frontline FL treatment from the US payer’s perspective. Progression risks, adverse event probabilities, costs, and utilities were estimated from clinical data of Primary RItuximab and MAintenance (PRIMA) trial, Eastern Cooperative Oncology Group (ECOG) trial (for MR), and First-line Indolent Trial (for RIT) and the published literature. We evaluated the incremental cost-effectiveness ratio for direct comparisons between MR/RIT and observation. Model robustness was addressed by one-way and probabilistic sensitivity analyses.ResultsCompared with observation, MR provided an additional 1.089 QALYs (1.099 LYs) and 1.399 QALYs (1.391 LYs) on the basis of the PRIMA trial and the ECOG trial, respectively, and RIT provided an additional 1.026 QALYs (1.034 LYs). The incremental cost per QALY gained was $40,335 (PRIMA) or$37,412 (ECOG) for MR and $40,851 for RIT. MR and RIT had comparable incremental QALYs before first progression, whereas RIT had higher incremental costs of adverse events due to higher incidences of cytopenias.ConclusionsMR and RIT following frontline FL therapy demonstrated favorable and similar cost-effectiveness profiles. The model results should be interpreted within the specific clinical settings of each trial. Selection of MR, RIT, or observation should be based on patient characteristics and expected trade-offs for these alternatives