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Page 14 of 25 Lue et al. J Cancer Metastasis Treat 2022;8:11 https://dx.doi.org/10.20517/2394-4722.2021.193

[127]
ORR of 55% (5/9) in patients with DLBCL , leading to a dose expansion trial in R/R DLBCL. In the
expanded component of this trial, 14 patients with MYC-altered DLBCL, defined as MYC translocated or
amplification with ≥3 copies in >20% of cells, were included with an observed ORR of 64% and median
[128]
duration of response (DOR) of 13.6 months . In a pooled analysis of phase I and phase II study of
fimepinostat, a total of 105 patients with R/R DLBCL were enrolled, of which 60 patients had MYC-
dysregulated DLBCL (classified as the presence of MYC translocation of MYC overexpression ≥ 40%). The
ORR was noted to be 23.3% (14/60), with a median time to response being 2.5 months . Given these
[129]
promising results in MYC-deregulated DLBCL, a phase I trial investigating the merits of fimepinostat in
conjunction with rituximab or venetoclax, or both (NCT01742988) is underway. Given the presence of
recurrent epigenetic dysregulation in GCB-DLBCL, pre-clinical and clinical investigation of potential
synergistic drug combinations involving multiple epigenetic agents and/or other small molecule
therapeutics is warranted.

Bromodomain and Extra-terminal (BET) proteins have also been linked to the activation of MYC and BCL2
signaling pathways, making it a rationale target for DHL . Pre-clinical studies have demonstrated that
[130]
treatment with JQ-1, an early BET inhibitor, and venetoclax, a BCL-2 inhibitor along with standard
vincristine or doxorubicin, led to significant growth delay of DHL/THL cells compared to single-agent
treatment . Moreover, exposure to CPI203, a BET inhibitor, can overcome acquired resistance to
[131]
[132]
venetoclax in pre-clinical DHL models , supporting the possible applicability of BET inhibitors for the
treatment of DLBCL, particularly DHL/THL. Although theoretically promising, several BET inhibitors have
entered clinical investigation, however, none to date have gained FDA approval.

The application of venetoclax for the treatment of DLBCL addresses chemotherapy resistance secondary to
BCL-2 overexpression, especially in patients with double expressor and DHL . Single-agent activity of
[133]
venetoclax in R/R DLBCL is modest, with a reported ORR of 18% . Recent studies have incorporated
[134]
venetoclax into the backbones of R-CHOP (CAVALLI study) and DA-EPOCH-R (ALLIANCE 51701
[135]
trial) , specifically targeting the DHL/Double Expresser populations. In the R/R setting, venetoclax is
[136]
being explored in various combinations including ibrutinib/rituximab (NCT03136497), RICE
(NCT03064867), Selinexor (NCT03955783), and ibrutinib/prednisone/obinutuzumab/revlimid
(NCT03223610, ViPOR). Ultimately the role of venetoclax in the treatment of DLBCL is yet to be firmly
established.

Therapeutics agents with activity irrespective of COO
Despite our advances in understanding the molecular heterogeneity of DLBCL, one can argue that perhaps
the fastest and smoothest approach to the advancement of DLBCL treatment would be to develop novel
drugs that can be applied across subtypes without the need for detailed molecular testing. This, of course,
would be a shift away from a precision medicine approach, a central theme in cancer treatment, but in the
real-world setting may be more applicable as it would overcome the hindrances and delays that often come
with the requirement of specific and sensitive assays. A primary example of this success would be
rituximab . Along those lines, novel antibody and antibody-drug conjugates have been developed for
[137]
lymphoid malignancies, including three recent FDA approvals in the R/R setting. Polatuzumab vedotin, an
antibody-drug conjugate against CD79b linked to monomethyl auristatin E, has been approved in
conjunction with rituximab and bendamustine (BR) after two failed therapies for transplant-ineligible
patients. A phase Ib/II study demonstrated both a superior CR rate (40% vs. 17.5%, P = 0.026) and median
[138]
OS (12.4 vs. 4.7 months; HR:0.42; 95%CI: 0.24-0.75, P=0.002) of polatuzumab-BR compared to BR alone .
Polatuzumab-vedotin has also been evaluated in combination with R-CHP (vincristine omitted due to
overlapping toxicities) in a randomized phase III trial for treatment-naive patients , resulting in a lower
[51]