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inhibition is used as induction, followed by R-CHOP, and concluding with PD1/PD-L1 inhibition
maintenance. The rationale behind this sequential therapy is to maximize the potential efficacy of PD1/PD-
L1 inhibition by avoiding corticosteroid-induced immunosuppression that could be observed when adding
immune checkpoint inhibition directly to the R-CHOP backbone. This is the approach that Hawkes and
colleagues adopted, where avelumab is combined with rituximab as induction, followed by R-CHOP x 6
[95]
cycles, and avelumab maintenance x 6 cycles . Induction with avelumab and rituximab x 2 cycles led to a
CR rate of 21% and ORR of 60%, followed by an ORR of 89% after six cycles of R-CHOP. Further studies
will be needed to fully elucidate the role of immune checkpoint inhibitors in the frontline setting for
DLBCL.

Targeting GC-DLBCL
Although patients with GCB-DLBCL generally have superior clinical outcomes compared to ABC-subtype,
approximately 20% of GCB patients will relapse following standard of care R-CHOP. Moreover, our
understanding of the molecular heterogeneity of DLBCL has revealed that DLBCLs with MYC-aberrations
tend to have an inferior prognosis compared to those who do not harbor MYC-derangements.
Approximately 5% to 14% of DLBCL cases have been reported to carry MYC translocations [28,96] , and of
those, 58% to 83% will also be characterized by a second or third translocation targeting BCL2 and/or BCL6,
which are referred to as DHL or THL, respectively [97-99] . In fact, DHL/THL patients have a median OS rate of
less than two years [27,100-102] . Moreover, MYC overexpression has also been associated with worse outcomes
[97]
after first-line R-CHOP , and can also be frequently observed in conjunction with BCL2 overexpression
(Double Expressors), which often coincide with an ABC-DLBCL categorization [27,29,103] . Thus, it has been
clearly established that R-CHOP therapy is suboptimal for the treatment of MYC-altered DLBCLs, and the
current treatment paradigm favors more dose-intense approaches, such as DA-EPOCH-R, (Dose-Adjusted-
Etoposide, Prednisone, Oncovorin, Cyclophophamide, Doxorubicin, Rituximab) in the upfront setting.

Pre-clinical data has demonstrated that the epigenome of GCB-DLBCL is dysregulated. Deregulation of
histone methyltransferases, such as EZH2 and mixed-lineage leukemia (MLL), have been associated with
the development of lymphomas, particularly GC-derived lymphomas [104-107] . Given the recognition of EZH2
activating mutation in GC-derived lymphomas, such as follicular lymphoma (FL) and DLBCL, EZH2
inhibitors have been developed based on single-agent activity observed in pre-clinical models of
DLBCL [104,108-119] . Tazemetostat, a first-in-human EZH2 inhibitor, has been FDA approved for the treatment
of R/R FL irrespective of mutational status. Despite initial promising responses observed in phase I
investigation, a dedicated phase II clinical trial of tazemetostat in conjunction with prednisolone in DLBCL
(NCT01897571) was closed after an interim assessment [120,121] . Clinical investigation of tazemetostat in
combination with R-CHOP is on-going at this time (EPI-RCHOP, NCT02889523). The addition of
tazemetostat thus far does not seem to compromise R-CHOP dose-intensity . Valemetostat, a dual
[122]
inhibitor of both EZH1 and EZH2, is postulated to have improved tumor suppression capabilities, and has
[123]
demonstrated an ORR of 53% (n = 15) in patients with R/R NHL (B and T-cell lymphoma) . These EZH2
inhibitors would be ideal targets for patients in the EZB MYC-negative and C3 subtypes.

Heterozygous loss of function mutations in histone acetyltransferases (HATs) such as CREBBP and EP300
are found in approximately 39% of DLBCL and FL and cooperate with BCL6 to promote
[124]
lymphomagenesis. The presence of CREBBP and EP300 haploinsufficiency has been associated with
response to histone deacetylase (HDAC) inhibitors in in vitro evaluations ; however, it is unclear if this
[125]
completely translates into the clinic. Nevertheless, single-agent HDAC inhibition for the treatment of
[126]
DLBCL has modest activity with a reported ORR of 17.1% after treatment with panobinostat .
Fimepinostat, a first-in-class dual HDAC and phosphoinositide 3-kinase (PI3K) inhibitor, demonstrated an