Leukemic Presentation and Progressive Genomic Alterations of MCD/C5 Diffuse Large B-cell Lymphoma (DLBCL)

Diffuse large B-cell lymphoma (DLBCL) is a very heterogenous group, subdivided into germinal-center (GC)-derived and activated B-cell (ABC) types. Advances in molecular methodologies, including whole exome sequencing (WES) and chromosomal microarrays (CMA), have fostered molecular subclassification of DLBCL, while improving our understanding of their pathogenic mechanisms and resistance to therapy. Here we present distinct case of de novo DLBCL that presented in leukemic form. WES revealed point mutations of CD79B, MyD88, TP53, TBL1XR1 and PIM1 genes, indicating that this lymphoma with leukemic presentation fits the best the MCD/C5 molecular subtype of DLBCL, the prominent subcategory of the ABC DLBCL. High-resolution CMA revealed amplification of genomic regions containing BTK, CCDN3, and PIM1 genes and loss of CDNK2A gene. Despite an initial good clinical response to BTK inhibitor ibrutinib, anti-CD20 antibody rituxan, alkylating agent bendamustine, and hematopoietic stem-cell transplant, the lymphoma relapsed, accompanied by morphologic and molecular evidence of disease progression. BTK and FOXO1 gene mutations emerged, indicative of ibrutinib and rituxan resistance, respectively, with CMA indicating also partial loss of BTK gene amplification. The recurrent tumor developed loss of TP53 heterozygosity and additional chromosomal changes, considered central to ABC DLBCL pathogenesis, such as PRDM1 loss. Finally, the relapsed lymphoma cells showed in vitro resistance to standard BTK inhibitors but sensitivity to vecabrutinib, active against mutated BTK, and to PIM1 inhibitor. In summary, we provide in-depth molecular characterization of a case representing leukemic form of DLBCL and discuss mechanisms that may have contributed to lymphoma progression and development of drug resistance.