Faculty Bibliography

Although chemotherapy has been a mainstay of the frontline treatment of mantle cell lymphoma (MCL) for many years, novel agents-including Bruton kinase inhibitors, immunomodulatory agents, and BCL2 inhibitors-have shown promise in patients with relapsed and refractory disease, and they are also being studied in the frontline setting. This review summarizes the current clinical data for using these novel agents in untreated MCL, both in combination with chemotherapy and singly, and discusses some of the trials currently under way to assess their future potential.

B-cell non-Hodgkin lymphomas (B-NHLs) are highly heterogenous by genetic, phenotypic, and clinical appearance. Next-generation sequencing technologies and multi-dimensional data analyses have further refined the way these diseases can be more precisely classified by specific genomic, epigenomic, and transcriptomic characteristics. The molecular and genetic heterogeneity of B-NHLs may contribute to the poor outcome of some of these diseases, suggesting that more personalized precision-medicine approaches are needed for improved therapeutic efficacy. The germinal center (GC) B-cell like diffuse large B-cell lymphomas (GCB-DLBCLs) and follicular lymphomas (FLs) share specific epigenetic programs. These diseases often remain difficult to treat and surprisingly do not respond advanced immunotherapies, despite arising in secondary lymphoid organs at sites of antigen recognition. Epigenetic dysregulation is a hallmark of GCB-DLBCLs and FLs, with gain-of-function (GOF) mutations in the histone methyltransferase EZH2, loss-of-function (LOF) mutations in histone acetyl transferases CREBBP and EP300, and the histone methyltransferase KMT2D representing the most prevalent genetic lesions driving these diseases. These mutations have the common effect to disrupt the interactions between lymphoma cells and the immune microenvironment, via decreased antigen presentation and responsiveness to IFN-γ and CD40 signaling pathways. This indicates that immune evasion is a key step in GC B-cell lymphomagenesis. EZH2 inhibitors are now approved for the treatment of FL and selective HDAC3 inhibitors counteracting the effects of CREBBP LOF mutations are under development. These treatments can help restore the immune control of GCB lymphomas, and may represent optimal candidate agents for more effective combination with immunotherapies. Here, we review recent progress in understanding the impact of mutant chromatin modifiers on immune evasion in GCB lymphomas. We provide new insights on how the epigenetic program of these diseases may be regulated at the level of metabolism, discussing the role of metabolic intermediates as cofactors of epigenetic enzymes. In addition, lymphoma metabolic adaptation can negatively influence the immune microenvironment, further contributing to the development of immune cold tumors, poorly infiltrated by effector immune cells. Based on these findings, we discuss relevant candidate epigenetic/metabolic/immune targets for rational combination therapies to investigate as more effective precision-medicine approaches for GCB lymphomas.

PURPOSE:SARS-CoV-2 (COVID-19) is a systemic infection. Patients with cancer are immunocompromised and may be vulnerable to COVID-related morbidity and mortality. The objectives of this study were to determine if patients with cancer have worse outcomes compared with patients without cancer and to identify demographic and clinical predictors of morbidity and mortality among patients with cancer. METHODS:We used data from adult patients who tested positive for COVID-19 and were admitted to two New York-Presbyterian hospitals between March 3 and May 15, 2020. Patients with cancer were matched 1:4 to controls without cancer in terms of age, sex, and number of comorbidities. Using Kaplan-Meier curves and the log-rank test, we compared morbidity (intensive care unit admission and intubation) and mortality outcomes between patients with cancer and controls. Among those with cancer, we identified demographic and clinical predictors of worse outcomes using Cox proportional hazard models. RESULTS:= .894) between patients with and without cancer. CONCLUSION:We observed that patients with COVID-19 and cancer had similar outcomes compared with matched patients without cancer. This finding suggests that a diagnosis of active cancer alone and recent anticancer therapy do not predict worse COVID-19 outcomes and therefore, recommendations to limit cancer-directed therapy must be considered carefully in relation to cancer-specific outcomes and death.

With the emerging application of novel targeted agents in the induction, maintenance and salvage strategies, management of aggressive mantle cell lymphoma is being transformed from high-intensity chemo-immunotherapy applicable to only selected patients, to more personalized treatment incorporating novel agents that are effective and accessible for the majority of the patients. This review summarizes risk-stratified management paradigm for aggressive mantle cell lymphoma, providing context for clinical applications of novel agents and cellular therapy including stem cell transplant and CAR-T.

PURPOSE OF REVIEW:IMiDs are a class of biologic agents with immunomodulatory, anti-angiogenic, and direct anti-cancer activities. This review summarizes current data on clinical development and application of IMiDs in non-Hodgkin lymphoma (NHL) subtypes, focusing primarily on lenalidomide, with additional discussion on managing common side effects. RECENT FINDINGS:Improved upon the prototype thalidomide, the second-generation compound lenalidomide has enhanced immunological and anti-cancer properties with fewer side effects, while next-generation small molecule cereblon/E3 ubiquitin ligase modulator CC-122 is in early clinical studies. Lenalidomide is FDA-approved for treatment of relapsed/refractory mantle cell lymphoma as a single agent, as well as in combination with rituximab for R/R follicular lymphoma and marginal zone lymphoma. In addition, numerous clinical trials of lenalidomide, as single agent, in combination with anti-CD20 antibodies, or in combination with chemoimmunotherapy regimens, have shown promise in aggressive and indolent NHL in both the upfront and relapsed/refractory setting. As clinical trials with lenalidomide continue to find success in both indolent and aggressive lymphomas, IMiDs are poised to be important building blocks for combinatorial strategies with antibodies, chemotherapy, novel target agents, and emerging immunotherapy involving immune checkpoint inhibitors and chimeric antigen receptor T cell (CAR-T) therapy. Delineation of treatment-specific and disease-specific biomarkers is an important research objective to gain insight into potential mechanisms of action, and to guide future clinical development.

Lenalidomide is associated with increased risk of thromboembolism (VTE) in patients with multiple myeloma. This risk has not previously been defined in B-cell non-Hodgkin lymphoma (NHL), for which lenalidomide is also an active agent. We conducted a systematic literature search in Ovid MEDLINE (1946 to February 2017), Ovid EMBASE (1974 to February 2017), The Cochrane Library (Wiley), and Web of Science Core Collection for prospective studies evaluating lenalidomide-containing regimens in B-cell NHL with adequate reporting of patient characteristics, total cycles received, and safety data including VTE rates. The primary outcome was VTE events per 100 patient-cycles by meta-analysis using random-effects models. Our literature search identified 1719 citations; 28 articles were included. For all patients with B-cell NHL receiving lenalidomide, the rate of VTE per 100 patient-cycles was 0.77 (95% confidence interval [CI], 0.48-1.12; I², 67%). The rate for single-agent lenalidomide was 1.09 events per 100 patient-cycles (95% CI, 0.49-1.94; I², 76%), the rate for lenalidomide plus biologics was 0.49 (95% CI, 0.17-0.97; I², 59%), and the rate for lenalidomide plus chemotherapy was 0.89 (95% CI, 0.39-1.60; I², 57%). Rate of VTE events in B-cell NHL patients treated with lenalidomide in clinical trials is similar to the rate in multiple myeloma. The VTE rate appears to be lowest for lenalidomide combined with a biologic compared with single-agent lenalidomide or its combination with chemotherapy. This protocol was registered at www.crd.york.ac.uk/prospero/ as #CRD42017056042.