Important Considerations in the Diagnosis and Management of Post-transplant Lymphoproliferative Disorder.

PURPOSE OF REVIEW: A relative lack of molecular and clinical studies compared to other lymphoid cancers has historically made it difficult to determine optimal management approaches in post-transplant lymphoproliferative disorder (PTLD). We sought to better define the "state of the science" in PTLD by examining recent advances in risk assessment, genomic profiling, and trials of PTLD-directed therapy. RECENT FINDINGS: Several major clinical trials highlight risk-stratified sequential therapy incorporating rituximab with or without chemotherapy as a rational treatment strategy in patients with CD20+ PTLD who do not respond to reduction of immunosuppression alone. Epstein Barr virus (EBV)-targeted cytotoxic lymphocytes are a promising approach in patients with relapsed/refractory EBV+ PTLD, but dedicated clinical trials should determine how autologous chimeric antigen receptor T cell therapy (CAR-T) may be safely administered to PTLD patients. Sequencing studies underscore the important effect of EBV infection on PTLD pathogenesis, but comprehensive genomic and tumor microenvironment profiling are needed to identify biomarkers that predict response to treatment in this clinically heterogeneous disease.

Improving eligibility criteria for first-line trials for patients with DLBCL using a US-based Delphi-method survey.

Recent first-line randomized controlled trials (RCTs) for patients with diffuse large B-cell lymphoma (DLBCL) have shown negative results, which may be due in part to onerous eligibility criteria limiting enrollment of poor-risk patients who require immediate treatment. We conducted a Delphi-method survey with lymphoma experts in the United States to define recommendations for essential and potentially unnecessary enrollment criteria for modern first-line DLBCL RCTs aimed at increasing clinical diversity of ensuing study groups. We first tabulated enrollment criteria from 19 DLBCL RCTs spanning the rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) era to identify common eligibility criteria from prior DLBCL RCTs for inclusion in the Delphi-method survey. We tabulated 451 total eligibility criteria comprising 51 criterion categories across 19 first-line DLBCL RCTs in the R-CHOP era. We then surveyed lymphoma clinical trial experts representing 8 academic medical centers in the United States regarding essential and unnecessary eligibility criteria for modern DLBCL RCTs. Seventeen of 29 invited clinical investigators completed the round-1 questionnaire (response rate, of 58.6%), 15 of 17 round-1 participants (88.2%) completed the round-2 survey, and all round-1 participants reviewed finalized recommendations for eligibility criteria for modern first-line DLBCL RCTs. We defined consensus recommendations for 31 modernized eligibility criteria including threshold values for 10 quantitative eligibility criteria aimed at facilitating enrollment of a clinically diverse study population in first-line DLBCL RCTs designed to improve standard-of-care therapy.

Genome-defined African ancestry is associated with distinct mutations and worse survival in patients with diffuse large B-cell lymphoma.

BACKGROUND: Significant racial differences have been observed in the incidence and clinical outcomes of diffuse large B-cell lymphoma (DLBCL) in the United States, but to the authors' knowledge it remains unclear whether genomic differences contribute to these disparities. METHODS: To understand the influences of genetic ancestry on tumor genomic alterations, the authors estimated the genetic ancestry of 1001 previously described patients with DLBCL using unsupervised model-based Admixture global ancestry analysis applied to exome sequencing data and examined the mutational profile of 150 DLBCL driver genes in tumors obtained from this cohort. RESULTS: Global ancestry prediction identified 619 patients with >90% European ancestry, 81 patients with >90% African ancestry, and 50 patients with >90% Asian ancestry. Compared with patients with DLBCL with European ancestry, patients with African ancestry were aged >10 years younger at the time of diagnosis and were more likely to present with B symptoms, elevated serum lactate dehydrogenase, extranodal disease, and advanced stage disease. Patients with African ancestry demonstrated worse overall survival compared with patients with European ancestry (median, 4.9 years vs 8.8 years; P = .04). Recurrent mutations of MLL2 (KMT2D), HIST1H1E, MYD88, BCL2, and PIM1 were found across all ancestry groups, suggesting shared mechanisms underlying tumor biology. The authors also identified 6 DLBCL driver genes that were more commonly mutated in patients with African ancestry compared with patients with European ancestry: ATM (21.0% vs 7.75%; P < .001), MGA (19.7% vs 5.33%; P < .001), SETD2 (17.3% vs 5.17%; P < .001), TET2 (12.3% vs 5.82%; P = .029), MLL3 (KMT2C) (11.1% vs 4.36%; P = .013), and DNMT3A (11.1% vs 4.52%; P = .016). CONCLUSIONS: Distinct prevalence and patterns of mutation highlight an important difference in the mutational landscapes of DLBCL arising in different ancestry groups. To the authors' knowledge, the results of the current study provide the first-ever characterization of genetic alterations among patients with African descent who are diagnosed with DLBCL.

Using Informatics Tools to Identify Opportunities for Precision Medicine in Diffuse Large B-cell Lymphoma.

INTRODUCTION: Diffuse large B-cell lymphoma (DLBCL) is genetically and clinically heterogeneous. Despite advances in genomic subtyping, standard frontline chemoimmunotherapy has remained unchanged for years. As high-throughput analysis becomes more accessible, characterizing drug-gene interactions in DLBCL could support patient-specific treatment strategies. MATERIALS AND METHODS: From our systematic literature review, we compiled a comprehensive list of somatic mutations implicated in DLBCL. We extracted reported and primary sequencing data for these mutations and assessed their association with signaling pathways, cell-of-origin subtypes, and clinical outcomes. RESULTS: Twenty-two targetable mutations present in ≥ 5% of patients with DLBCL were associated with unfavorable outcomes, yielding a predicted population of 31.7% of DLBCL cases with poor-risk disease and candidacy for targeted therapy. A second review identified 256 studies that had characterized the drug-gene interactions for these mutations via in vitro studies, mouse models, and/or clinical trials. CONCLUSIONS: Our novel approach linking the data from our systematic reviews with informatics tools identified high-risk DLBCL subgroups, DLBCL-specific drug-gene interactions, and potential populations for precision medicine trials.

Cost-effectiveness of New Targeted Agents in the Treatment of Chronic Lymphocytic Leukemia.

Chronic lymphocytic leukemia (CLL) is the most common adult leukemia and is clinically heterogeneous. Integration of oral targeted therapies (OTTs) in the management of CLL has fundamentally altered CLL treatment pathways and improved outcomes for patients with CLL.We review the cost-effectiveness of OTTs in the treatment of CLL. We used MeSH (Medical Subject Heading) terms and keywords to search the National Library of Medicine online MEDLINE database (PubMed) for articles related to cost-effectiveness of OTTs in CLL care.Oral targeted therapies add considerable expense to the treatment of CLL for patients and the health care system. Cost-effectiveness analyses of OTTs are not uniform in their conclusions and depend on patient groups selected for analysis. Given the substantial increase in expense associated with integration of OTTs in CLL treatment, cost reduction methods are needed to ensure equitable access to novel therapies for all patients with CLL.

Cost burden of diffuse large B-cell lymphoma.

Introduction: Diffuse large B-cell lymphoma (DLBCL) is the most common non-Hodgkin lymphoma and is a clinically heterogeneous disease. Treatment pathways for DLBCL are diverse and integrate established and novel therapies.Areas covered: We review the cost burden of DLBCL and the cost-effectiveness of DLBCL management including precision and cellular medicine. We utilized Medical Subject Heading (MeSH) terms and keywords to search the National Library of Medicine online MEDLINE database (PubMed) for articles related to cost, cost burden, and cost-of-illness of DLBCL and cost-effectiveness of DLBCL management strategies published in English as of June 2019.Expert commentary: Available and developing DLBCL therapies offer improved outcomes and often curative treatment at considerable financial expense, and the total cost burden for DLBCL management is substantial for patients and the healthcare system. In the era of personalized medicine, CAR T cells and targeted therapies provide exciting avenues for current and future DLBCL care and can further increase treatment cost. Determinations of cost and cost-effectiveness in DLBCL treatment pathways should continue to guide care providers and systems in identifying cost reduction strategies to provide appropriate therapies to the greatest number of patients in treating DLBCL.

Remaining challenges in predicting patient outcomes for diffuse large B-cell lymphoma.

Introduction: Diffuse large B-cell lymphoma (DLBCL) is the most common non-Hodgkin lymphoma and is an aggressive malignancy with heterogeneous outcomes. Diverse methods for DLBCL outcomes assessment ranging from clinical to genomic have been developed with variable predictive and prognostic success.Areas covered: The authors provide an overview of the various methods currently used to estimate prognosis in DLBCL patients. Models incorporating cell of origin, genomic features, sociodemographic factors, treatment effectiveness measures, and machine learning are described.Expert opinion: The clinical and genetic heterogeneity of DLBCL presents distinct challenges in predicting response to therapy and overall prognosis. Successful integration of predictive and prognostic tools in clinical trials and in a standard clinical workflow for DLBCL will likely require a combination of methods incorporating clinical, sociodemographic, and molecular factors with the aid of machine learning and high-dimensional data analysis.