“Cytogenetic/FISH studies may identify MYC, BCL2 and/or BCL6 translocations, which defines a double- (or triple-) hit B cell lymphoma,” Dr Aguiar told Cancer Therapy Advisor. These tumors respond poorly to R-CHOP, so more intensive induction regimens should be considered, like dose-adjusted rituximab plus etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin (DA-R-EPOCH).
“We caution, however, that there are no firm guidelines from prospective trials for the treatment of double-hit lymphoma, and patients should be ideally treated in the context of a clinical trial,” Dr Aguiar added. “It also important to note that the World Health Organization (WHO) classification already recognizes these lymphomas as separate from DLBCL; they are named ‘High grade B cell lymphoma with translocations involving MYC and BCL2 or BCL6.‘”
Molecularly characterized ABC-like DLBCLs are also less likely to respond to R-CHOP, Dr Aguiar said.
“Patients diagnosed with this subtype of DLBCL should be given the opportunity to enroll in clinical trials, in particular in studies that include BCR-related kinase inhibitors,” he advised. “It is important to stress, however, that R-CHOP remains the first-line treatment for DLBCL regardless of its molecular subtype, and that all other regimens should be considered experimental and conducted in a clinical trial setting.”
More recently, the prognostic significance of MYC and BCL2 co-expression, assessed using IHC, was established. These are called dual-expressor (DE) DLBCLs and are associated with very poor prognosis, Dr Aguiar said. It is likely that MYC and BCL2 are causally involved in the poor outcome, although that has yet to be demonstrated empirically.
“These tumors should be distinguished from double-hit lymphomas because they do not have chromosomal translocations involving MYC and BCL2, although they may harbor 1 of the 2 translocations,” he explained.
Promising investigational treatments include PD-1/PD-L1 immune checkpoint inhibitors for DLBCL tumors in testicular, central nervous system, or mediastinal tissues and organs.
“A large fraction of these tumors display amplification — and less frequently, translocations — of chromosome 9p24, which encompass the PD-L1 (and PD-L2) loci,” Dr Aguiar noted. “These ligands are consequently overexpressed in the tumor cells, which likely dampens the T cell mediated anti-tumor immunity, rendering these patients particularly responsive to checkpoint inhibitors.”
Chimeric antigen receptor (CAR)-T cell therapies are also “becoming a very valid therapeutic strategy for relapsed/refractory patients who have few options outside ASCT [autologous stem cell transplant],” Dr Aguiar noted. “The field should perhaps focus now on identifying biological markers of response, validate other antigen targets (eg, CD20), and increase access to this therapeutic modality beyond larger cancer centers.”
Continued, deliberate exploration of the molecular pathways involved in different subsets of the disease is crucial to achieve clinical advances in the future.
“DLBCL is a remarkably heterogeneous disease,” Dr Aguiar said. “It is likely that a road for cure in this disease will require the mapping all of DLBCL dependencies (and hence, its vulnerabilities), and the development of novel targeted strategies that are uniquely effective to specific subsets of tumor.
“Thus, while rapid clinical translation is much desired, perhaps the bulk of the investment and effort should remain directed at basic studies, towards the precise understanding of the molecular and cellular basis of DLBCL.”
- Butler MJ, Aguiar RCT. Biology informs treatment choices in diffuse large B cell lymphoma. Trends Cancer. In press. doi: 10.1016/j.trecan.2017.09.008
- Sujobert P, Salles G, Bachy E. Molecular classification of diffuse large B-cell lymphoma: what is clinically relevant? Hematol Oncol Clin N Am. 2016;30:1163-77. doi: 10.1016/j.hoc.2016.07.001