Page 182 - 2020_11-Haematologica-web

2670
Letters to the Editor
inferior prognosis among GCB-DLBCL. This tumor sub- group was characterized by a gene expression signature derived from HGBL-DH/TH lymphomas (DHIT signa- ture).8 Using this signature, however, only 50% of the cases stratified into the subgroup actually had dual rearrangements of MYC and BCL-2 genes, and some DE cases were not assigned into the DHIT signature positive group. Gene set enrichment analysis demonstrated (over-) expression of MYC and E2F target genes, and of genes associated with oxidative phosphorylation and MTORC1 signaling in the DHIT-positive tumors, imply- ing a pivotal role for MYC protein expression irrespective of the DH status. Unfortunately, the study did not docu- ment the precise percentage of MYC protein expression; it also did not correlate MYC protein expression to MYC gene rearrangements. The second paper identified 9% of DLBCL (83 of 928) as “molecular high grade (MHG)” B- cell lymphomas using gene expression analysis.9 Most MHG (75 of 83) were GCB-like, and again, only half of them were MYC rearranged or double-hit lymphomas. The MHG subset treated with R-CHOP had a significant- ly poorer outcome than MHG negative DLBCL. Furthermore, in vivo experiments demonstrated that MYC-expressing lymphoma cells were obviously addict- ed to its oncogenic effect and, therefore, were critically relying on MYC expression regardless of MYC gene rearrangements.10
Although genomic testing has entered clinical practice, sophisticated tests like those reported are not yet widely available in all laboratories. Therefore, gene expression signatures identifying high-risk subgroups are currently difficult to apply in the clinic. Our findings describe a more readily available tool to identify patients at risk with a high MYC protein expression cut-off circumvent- ing problems related to interobserver variability.11 Our findings are corroborated in a recent paper by Pedersen et al.12 who demonstrated that stratification by MYC expression has prognostic impact in MYC translocated DLBCL.12
In summary, we have confirmed that the prognosis of DLBCL is inversely correlated with MYC protein expres- sion levels, and, by using diagnostic thresholds of high reproducibility, we were able to identify a subset of patients with adverse outcome in need of alternative therapeutic strategies.
Marita Ziepert,1 Stefano Lazzi,2 Raffaella Santi,3
Federica Vergoni,3 Massimo Granai,2 Virginia Mancini,2 Annette M. Staiger,4,5 Heike Horn,4,5 Markus Löffler,6 Viola Pöschel,7 Gerhald Held,7 Gerald Wulf,8 Lorenz H. Trümper,9 Norbert Schmitz,10 Andreas Rosenwald,11 Elena Sabattini,12 Kikkeri N. Naresh,13 Harald Stein,14 German Ott4
and Lorenzo Leoncini2
1University of Leipzig - Institute of Medical Informatics, Statistics and Epidemiology, Leipzig, Germany; 2Department of Medical Biotechnology, Section of Pathology, University of Siena, Siena, Italy; 3Department of Pathology, Careggi University Hospital, University of Firenze, Firenze, Italy; 4Department of Clinical Pathology, Robert- Bosch-Krankenhaus, Stuttgart, Germany; 5Dr. Margarete Fischer- Bosch-Institute of Clinical Pharmacology, Stuttgart, Germany and University of Tübingen, Germany; 6Institute for Medical Informatics,
Statistics and Epidemiology, University of Leipzig, Leipzig, Germany; 7DSHNHL Studiensekretariat, Universitätsklinikum des Saarlandes, Homburg, Germany; 8Department of Hematology and Oncology, Georg-August Universität, Göttingen, Germany; 9G-CCC (Göttingen Comprehensive Cancer Center), University Medicine Göttingen, Göttingen, Germany; 10Department of Medicine A, University Hospital Münster, Münster, Germany; 11Institute
of Pathology, Universität Würzburg and Comprehensive Cancer Center Mainfranken (CCCMF), Würzburg, Germany; 12Institute
of Hematology "L. and A. Seràgnoli", S. Orsola - Malpighi Hospital, Bologna, Italy; 13Hammersmith Hospital and Imperial College, London, UK; 14Pathodiagnostik Berlin, Berlin, Germany and 15Department of Clinical Pathology, Robert-Bosch-Krankenhaus, Stuttgart, Germany
Correspondence:
LORENZO LEONCINI - lorenzo.leoncini@dbm.unisi.it
doi:10.3324/haematol.2019.235556
References
1. Ambrosio MR, Lazzi S, Lo Bello G, et al. MYC protein expression scoring and its impact on the prognosis of aggressive B-cell lym- phoma patients. Haematologica. 2019;104(1):e25-e28
2. Staiger AM, Altenbuchinger M, Ziepert, et al. A novel lymphoma- associated macrophage interaction signature (LAMIS) provides robust risk prognostication in diffuse large B-cell lymphoma clinical trial cohorts of the DSHNHL. Leukemia. 2019;34(2):543-552.
3. MellertK,MartinM,LennerzJK,etal.TheimpactofSOCS1muta- tions in diffuse large B-cell lymphoma. Br J Haematol. 2019;187(5):627-637
4. SchmitzN,NickelsenM,ZiepertM,etal.Conventionalchemother- apy (CHOEP-14) with rituximab or high-dose chemotherapy (MegaCHOEP) with rituximab for young, high-risk patients with aggressive B-cell lymphoma: an open-label, randomised, phase 3 trial (DSHNHL 2002-1). Lancet Oncol. 2012;13(12):1250-1259
5. Pfreundschuh M, Trümper L, Osterborg A, et al. CHOP-like chemotherapy plus rituximab versus CHOP-like chemotherapy alone in young patients with good-prognosis diffuse large-B-cell lym- phoma: a randomised controlled trial by the MabThera International Trial (MInT) Group. Lancet Oncol. 2006;7(5):379-391.
6. Cunningham D, Hawkes EA, Jack A, et al. Rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisolone in patients with newly diagnosed diffuse large B-cell non-Hodgkin lym- phoma: a phase 3 comparison of dose intensification with 14-day versus 21-day cycles. Lancet. 2013;25;381(9880):1817-1826.
7. Hupp M, Williams S, Dunnette B, et al. Comparison of evaluation techniques, including digital image analysis, for MYC protein expres- sion by immunohistochemical stain in aggressive B-cell lymphomas. Hum Pathol. 2019;83:124-132.
8. Ennishi D, Jiang A, Boyle M, et al. Double-hit gene expression signa- ture defines a distinct subgroup of germinal center B-cell-like diffuse large B-cell lymphoma. J Clin Oncol. 2019;37(3):190-201.
9. Sha C, Barrans S, Cucco F, et al. Molecular high-grade B-cell lym- phoma: defining a poor-risk group that requires different approaches to therapy. J Clin Oncol. 2019;37(3):202-212.
10. LiW,GuptaSK,HanW,etal.TargetingMYCactivityindouble-hit lymphoma with MYC and BCL2 and/or BCL6 rearrangements with epigenetic bromodomain inhibitors. J Hematol Oncol. 2019;12(1):73.
11. MahmoudAZ,GeorgeTI,CzuchlewskiDR,etal.ScoringofMYC protein expression in diffuse large B-cell lymphomas: concordance rate among hematopathologists. Mod Pathol. 2015;28(4):545-551.
12. Pedersen MØ, Gang AO, Clasen-Linde E, et al. Stratification by MYC expression has prognostic impact in MYC translocated B-cell lymphoma identifies a subgroup of patients with poor outcome. Eur J Haematol. 2019;102(5):395-406.
haematologica | 2020; 105(11)