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Targetable subsets of non-Hodgkin lymphoma in Malawi define therapeutic opportunities.

ABSTRACT: Diagnostics and supportive care for patients with non-Hodgkin lymphoma (NHL) in lower- and middle-income countries (LMICs) are lacking. We hypothesized that high-throughput transcription-based diagnostics could classify NHL specimens from Malawi amenable to targeted therapeutics. We established tissue microarrays and classified 328 cases diagnosed by hematoxylin and eosin as NHL at University of Malawi College of Medicine using immunohistochemistry (IHC) for conventional markers and therapeutic targets. A subset was analyzed using NanoString-based expression profiling with parsimonious transcriptional classifiers. Overall, 72% of lymphomas were high-grade B-cell tumors, subsets of which were enriched for expression of MYC, BCL2, and/or PD-L1. A 21-gene transcriptional classifier, previously validated in Western cohorts, divided 96% of diffuse large B-cell lymphomas (DLBCLs) with 100% of B-cell lymphomas, unclassifiable, into 1 cluster and 88% of Burkitt lymphomas into a separate cluster. Cell-of-origin categorization of 36 DLBCLs by NanoString lymphoma subtyping test (LST) revealed 69% concordance with IHC. All discordant cases were classified as germinal center B cell-like (GCB) by LST but non-GCB by IHC. In summary, utilization of advanced diagnostics facilitates objective assessment and segregation of biologically defined subsets of NHL from an LMIC without expert review, thereby establishing a basis for the implementation of effective and less toxic targeted agents.

SUBMITTER: Morgan EA

PROVIDER: S-EPMC5744047 | biostudies-literature | 2016 Nov

REPOSITORIES: biostudies-literature

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Targetable subsets of non-Hodgkin lymphoma in Malawi define therapeutic opportunities.

Morgan Elizabeth A EA Sweeney M Patrick MP Tomoka Tamiwe T Kopp Nadja N Gusenleitner Daniel D Redd Robert A RA Carey Christopher D CD Masamba Leo L Kamiza Steve S Pinkus Geraldine S GS Neuberg Donna S DS Rodig Scott J SJ Milner Danny A DA Weinstock David M DM

Blood advances 20161122 1

Diagnostics and supportive care for patients with non-Hodgkin lymphoma (NHL) in lower- and middle-income countries (LMICs) are lacking. We hypothesized that high-throughput transcription-based diagnostics could classify NHL specimens from Malawi amenable to targeted therapeutics. We established tissue microarrays and classified 328 cases diagnosed by hematoxylin and eosin as NHL at University of Malawi College of Medicine using immunohistochemistry (IHC) for conventional markers and therapeutic ...[more]

PMID: 29296697

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Project description:BackgroundNon-Hodgkin lymphoma (NHL) comprises biologically and clinically heterogeneous subtypes. Previously, study size has limited the ability to compare and contrast the risk factor profiles among these heterogeneous subtypes.MethodsWe pooled individual-level data from 17 471 NHL cases and 23 096 controls in 20 case-control studies from the International Lymphoma Epidemiology Consortium (InterLymph). We estimated the associations, measured as odds ratios, between each of 11 NHL subtypes and self-reported medical history, family history of hematologic malignancy, lifestyle factors, and occupation. We then assessed the heterogeneity of associations by evaluating the variability (Q value) of the estimated odds ratios for a given exposure among subtypes. Finally, we organized the subtypes into a hierarchical tree to identify groups that had similar risk factor profiles. Statistical significance of tree partitions was estimated by permutation-based P values (P NODE).ResultsRisks differed statistically significantly among NHL subtypes for medical history factors (autoimmune diseases, hepatitis C virus seropositivity, eczema, and blood transfusion), family history of leukemia and multiple myeloma, alcohol consumption, cigarette smoking, and certain occupations, whereas generally homogeneous risks among subtypes were observed for family history of NHL, recreational sun exposure, hay fever, allergy, and socioeconomic status. Overall, the greatest difference in risk factors occurred between T-cell and B-cell lymphomas (P NODE < 1.0×10(-4)), with increased risks generally restricted to T-cell lymphomas for eczema, T-cell-activating autoimmune diseases, family history of multiple myeloma, and occupation as a painter. We further observed substantial heterogeneity among B-cell lymphomas (P NODE < 1.0×10(-4)). Increased risks for B-cell-activating autoimmune disease and hepatitis C virus seropositivity and decreased risks for alcohol consumption and occupation as a teacher generally were restricted to marginal zone lymphoma, Burkitt/Burkitt-like lymphoma/leukemia, diffuse large B-cell lymphoma, and/or lymphoplasmacytic lymphoma/Waldenström macroglobulinemia.ConclusionsUsing a novel approach to investigate etiologic heterogeneity among NHL subtypes, we identified risk factors that were common among subtypes as well as risk factors that appeared to be distinct among individual or a few subtypes, suggesting both subtype-specific and shared underlying mechanisms. Further research is needed to test putative mechanisms, investigate other risk factors (eg, other infections, environmental exposures, and diet), and evaluate potential joint effects with genetic susceptibility.

Project description:Non-Hodgkin's lymphoma (NHL) is a cancer that starts in the lymphatic system. In NHL, the important part of the immune system, a type of white blood cells called lymphocytes become cancerous. NHL subtypes include marginal zone lymphoma, small lymphocytic lymphoma, follicular lymphoma (FL), and lymphoplasmacytic lymphoma. The disease can emerge in either aggressive or indolent form. 5-year survival duration after diagnosis is poor among patients with aggressive/relapsing form of NHL. Therefore, it is necessary to understand the molecular mechanisms of pathogenesis involved in NHL establishment and progression. In the next step, we can develop innovative therapies for NHL based on our knowledge in signaling pathways, surface antigens, and tumor milieu of NHL. In the recent few decades, several treatment solutions of NHL mainly based on targeted/directed therapies have been evaluated. These approaches include B-cell receptor (BCR) signaling inhibitors, immunomodulatory agents, monoclonal antibodies (mAbs), epigenetic modulators, Bcl-2 inhibitors, checkpoint inhibitors, and T-cell therapy. In recent years, methods based on T cell immunotherapy have been considered as a novel promising anti-cancer strategy in the treatment of various types of cancers, and particularly in blood cancers. These methods could significantly increase the capacity of the immune system to induce durable anti-cancer responses in patients with chemotherapy-resistant lymphoma. One of the promising therapy methods involved in the triumph of immunotherapy is the chimeric antigen receptor (CAR) T cells with dramatically improved killing activity against tumor cells. The CAR-T cell-based anti-cancer therapy targeting a pan-B-cell marker, CD19 is recently approved by the US Food and Drug Administration (FDA) for the treatment of chemotherapy-resistant B-cell NHL. In this review, we will discuss the structure, molecular mechanisms, results of clinical trials, and the toxicity of CAR-T cell-based therapies. Also, we will criticize the clinical aspects, the treatment considerations, and the challenges and possible drawbacks of the application of CAR-T cells in the treatment of NHL.

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Targetable subsets of non-Hodgkin lymphoma in Malawi define therapeutic opportunities.

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Targetable subsets of non-Hodgkin lymphoma in Malawi define therapeutic opportunities.

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