A new stromal signature applicable to formalin-fixed paraffin-embedded tissues identifies patients at risk in prospective clinical trials of the German High-Grade Non-Hodgkin Lymphoma Study Group

ASH: 60th American Society of Hematology Annual Meeting & ExpositionAM Staiger, M Altenbuchinger, M Ziepert, C Kohler, H Horn, M Huttner, K Huettl, W Klapper, M Szczepanowski, J Richter, A Rosenwald, H Stein, A Feller, P Moeller, M-L Hansmann, M Loeffler, V Poeschel, G Held, L Truemper, G Ott, R Spang | December 02, 2018

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Summary: These researchers developed a new stromal signature applicable to formalin-fixed paraffin-embedded (FFPE) tissues to identify patients with diffuse large B-cell-lymphoma (DLBCL) who may be at risk in prospective clinical trials of the German High-Grade Non-Hodgkin Lymphoma Study Group. Their results suggest that the composition and quality of the tumor stroma are independent risk factors for DLBCL, and highlight the importance of the tumor microenvironment in the prognostic stratification of these patients.

Methods:

  • Researchers constructed a molecular signature applicable to formalin-fixed paraffin-embedded (FFPE), to ascertain the quantitative and qualitative composition of the microenvironment in diffuse large B-cell-lymphoma (DLBCL).
  • To train the signature, they used an algorithm that extracts prognostic information out of the ratios of pairs of genes becuase genes that drive prognosis are expressed in T-cells and macrophages and have function in the communication between both cell types.
  • Researchers validated the model using the NanoString assay in a cohort of 466 DLBCL patients enrolled in 7 prospective clinical trials (MInT, MegaCHOEP phase III and observation, RICOVER-60, RICOVER-noRTh, DENSER, SMARTER) of the German High grade non-Hodgkin’s lymphoma study group (DSHNHL).

Results:

  • Researchers grouped patients into quartiles according to the expression of the continuous stromal signature score (ranging from -1.880 to 4.441).
  • The result was three quartiles (Q1-3) that exhibited comparable clinical behavior (low stromal signature).
  • Patients from quartile 4 (Q4), which was characterized by high expression of the signature (stromal signature high), showed a clearly inferior outcome in event-free survival (EFS), progression-free survival (PFS) and overall survival (OS); which was independently reproduced in these seven clinical trials and clearly showed the robustness of the signature.
  • Upon multivariate analysis, researchers observed that a high expression of the stromal signature is a prognostic risk factor independent of the IPI factors in EFS (HR: 1.7, 95% CI: 1.2-2.4, P=001), PFS (HR: 1.8, 95% CI: 1.2-2.5, P=0.001) and OS (HR: 1.8, 95% CI: 1.3-2.7, P=0.001).
  • When they combined stromal signature count with IPI-score, they were able to identify a high-risk cohort.
  • When they performed additional multivariate analyses adjusted for the IPI factors performed within selected trials, they found that the stromal signature provides prognostic information independent of the cell of origin (COO) status, MYC and dual MYC/BCL2 rearrangements, TP53 mutations and the MYC/BCL2 double expresser status. 

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