Sandeep Dave

This chapter describes the clinical, pathological, and genetic characteristics of enteropathy-associated T-cell lymphoma (EATL), monomorphic epitheliotropic intestinal T-cell lymphoma, and refractory celiac disease (RCD), a rare lymphoproliferative disorder that is a precursor to a subset of EATLs. It discusses current and emerging treatment options. Epidemiologic studies indicate a low prevalence of RCD in the community. In contrast to EATL, a female predominance is observed in RCD. Chemotherapy and stem-cell transplantation have been used for refractory RCD II, but these therapies have shown limited benefit with regard to long term disease control and are associated with substantial adverse effects. Future studies need to identify genetic and other risk factors for the progression of RCD to EATL.

Mantle cell lymphoma (MCL) is a rare and aggressive form of B-cell non-Hodgkin lymphoma (NHL). Approximately 40%-50% of MCL patients carry inactivating mutations in the gene ataxia telangiectasia mutated (ATM), a core component of the cell's DNA damage response system. MCL cells with mutations in ATM are known to have increased chromosomal imbalance, copy number loss, and hypersensitivity to DNA-damaging agents. LP-184, a small-molecule DNA-damaging agent, is known to be synthetically lethal in tumors with DNA-repair deficiencies, including tumors with ATM mutations. However, DNA damage by LP-184 is dependent on activation by the oxidoreductase prostaglandin reductase 1 (PTGR1), which is expressed at low levels in many hematological cancers. We synthesized LP-284, an enantiomer of LP-184, which retains synthetic lethality in cancers with impaired DNA damage repair pathway genes (e.g., ERCC1, ERCC2, ERCC3, ERCC6), but LP-284's activity is independent of PTGR1 expression. We demonstrated that LP-284 has enhanced tumoricidal activity in multiple hematological cancer cell lines using a B-cell NHL panel. The IC50 values for all 6 MCL cell lines treated with LP-284 were among the lowest for all hematological cell lines tested with LP-284. These MCL cell lines included cell lines resistant to ibrutinib, zanubrutinib, venetoclax, and bortezomib. Additionally, among the 6 MCL cell lines tested, the 3 cell lines with mutations in the nucleotide excision repair (NER) or homologous recombination (HR) DNA damage repair pathways had lower LP-284 IC50 values than the 3 cell lines without NER or HR mutations. Because ATM orchestrates the activities of the NER and HR pathways, MCL patients with ATM deficiencies are likely to have better responses to LP-284 treatment. Collectively, these data indicate that LP-284 is a promising preclinical DNA-damaging agent that possesses nanomolar-range anti-tumor activities in multiple and diverse MCL cell lines, with the potential to treat MCL patients who are resistant to other therapies.

Epstein-Barr virus (EBV) is one of the most common viruses associated with multiple malignancies including hematopoietic, epithelial, and mesenchymal neoplasms. EBV is linked to B- and T-cell lymphomas, ranging from indolent to highly aggressive neoplasms. EBV-positive follicular lymphoma (FL) is not well characterized due to its low prevalence. In this report, we describe a case of EBV-positive FL and concurrent EBV-negative diffuse large B-cell lymphoma (DLBCL), and discuss their clonal relationship, and EBV status in the process of disease progression. Histology, immunohistochemistry, in situ hybridization, and next-generation sequencing studies were performed as previously described. The 58-year-old male presented with extensive axillary and subpectoral lymphadenopathy. The patient had a history of mixed connective tissue disease treated in the past with steroids and methotrexate, and at the time of current presentation with hydroxychloroquine. The excision of axillary lymph node showed coexistent EBV-positive FL (grade 3B) and EBV-negative DLBCL. There was no evidence of BCL2 gene rearrangement; however, both EBV-positive neoplastic follicles and diffuse component harbored MYC/IGH rearrangement. Next-generation sequencing suggested branching evolution with shared DDX3X mutation, a number of private mutations, and unique IGH usage in FL and DLBCL. The patient was treated with six cycles of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone) with involved-field radiotherapy and remains in complete remission. To the best of our knowledge, this is the first report of BCL2 rearrangement negative, MYC/IGH-positive and EBV-positive FL, and concurrent EBV-negative DLBCL, which supports branched evolution model.

Lymphoma is the sixth most common cause of cancer death in any individual person in the United States and there are over 50 recognized individual lymphoma pathologic entities. Even within relatively common entities such as diffuse large B-cell lymphoma, there are subgroups now defined by gene expression signatures and other genomic markers. Advances in our understanding of the genomic underpinnings of these diseases have led the design of novel therapeutic strategies that have begun to change the outcome for patients that cannot be cured with standard therapies. This chapter reviews our current understanding of the genomic alterations in the most common lymphoma subtypes and discusses recent approaches in precision medicine for lymphomas.