In this issue of Blood, Ramos et al present the results of a randomized phase 2 trial that tested the addition of the oral histone deacetylase (HDAC) inhibitor vorinostat to standard rituximab plus etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin (R-EPOCH) for patients with HIV-associated diffuse large B-cell lymphoma (DLBCL). Although it was solidly based on preclinical data supporting the concept that an HDAC inhibitor would add efficacy in tumors that often harbor Epstein-Barr virus in the setting of HIV infection, it did not translate into a better result in the clinic, at least with this HDAC inhibitor combined with the R-EPOCH backbone. The complete remission (CR) rates with R-EPOCH (74%) vs R-EPOCH with vorinostat (68%) (P = .72) and the overall survival (OS) and event-free survival (EFS) rates were similar between arms.1 

So what can be learned from this study about what matters in HIV-associated aggressive lymphoma? MYC protein expression in the tumor cell matters. MYC is a transcription factor that provides a proliferation stimulus. It is assessed in DLBCL by immunohistochemistry along with BCL2 whose presence enables the cell to avoid apoptosis. The expression of both proteins is referred to as double expression (DE). MYC translocations are assessed with fluorescence in situ hybridization (FISH), and when MYC moves to an immunoglobulin gene or to BCL6, it is referred as a double hit lymphoma (DHIT) or a triple hit lymphoma (THIT). FISH can also detect amplification of MYC. Both DE2  and DHIT or THIT3,4  tumors are associated with an adverse prognosis; MYC amplification by itself is neutral.5  Indeed, patients in the Ramos et al study with Myc expression >40% in the tumor had significantly lower EFS rates (44% at 3 years vs 83% in Myc-DLBCL). In a recent trial of dose adjusted R-EPOCH in DLBCL patients without HIV infection, patients with MYC protein–positive tumors did worse by 10%.6  Therefore, MYC protein matters not only in HIV-associated DLBCL but also in ordinary DLBCL.

The blood CD4 count at baseline also had consequences. The median baseline CD4 cell count was 190 cells per cubic millimeter. Eighty-five percent of patients with a CD4 count >200 achieved CR compared with only 45% if the absolute CD4 count was <100. This parameter is not typically reported in large series of DLBCL patients who do not have HIV. A surrogate for the CD4 count is the absolute lymphocyte count (ALC), and a low ALC is associated with inferior outcome in DLBCL.7  The use of CD4 counts as eligibility factors in DLBCL studies varies. For example, in the Alliance/CALGB 50303 study, HIV-positive patients were ineligible.6  In the recently completed E1412 study,8  patients with HIV were required to have a CD4 count >400, a level that most patients in the Ramos et al study did not achieve (median absolute CD4 count of only 190).

The presence of the HIV infection was important. Patients with HIV-associated aggressive lymphomas treated with regimens based on R-EPOCH have an OS at 2 years of 76% compared with 86% in Bartlett et al.6  The diagnosis-to-treatment interval (DTI) was confirmed to be important in HIV-associated DLBCL, just like it is in DLBCL that is not associated with HIV.9  A short DTI (<15 days) was associated with a lower CR rate (57% vs 86%; P = .003).

Which of the lessons learned from this trial can be applied to the next trials in aggressive non-Hodgkin lymphoma (NHL)? First, consider the workup and initiation of treatment for DLBCL on clinical trials as an urgent medical situation. To capture and enroll high-risk patients, prephase treatment (as performed in the Ramos et al trial) should be allowed. Rapid pathology prereview to confirm diagnosis and the availability of tissue for biomarker analysis is required, and E1412 showed that this is indeed feasible in the National Clinical Trials Network (NCTN) setting.10  The workup should include immunohistochemistry for Myc and BCL2 protein, determination of cell of origin, FISH testing for a DHIT or THIT tumor, and mutation analyses for specific genes of interest that are relevant to the new agent being tested. CD4 counts (or ALC as a surrogate) are also important. It should be possible to test for these biomarkers within 1 cycle (3 weeks); randomization and stratification can occur at cycle 2.

Second, given that MYC and BCL2 are important in the prognosis, the new agents selected for testing should be relevant to those targets. An example of this is the new NCTN trial (NCT03984448) for patients with tumors that have MYC and BCL2 abnormalities as evidenced by DE or by DHIT or THIT tumors. Because venetoclax targets BCL2, this trial will test whether it can add benefit to standard rituximab chemotherapy for this specific group of patients.

Third, given these results and the plethora of new agents available to test, it may be possible to increase the treatment opportunities for patients with HIV-associated aggressive NHL by enabling them to enroll on mainstream NHL protocols. The Ramos et al study was a collaborative effort between the AIDS Malignancy Consortium and the National Cancer Institute, and it required 7.5 years to accrue 91 patients at 21 sites (an accrual rate of 12 patients per year [less than 1 patient per site per year]). Another more efficient way might be to create a separate arm in these new NCTN trials for immunosuppressed individuals. This leverages the new agents and the extensive network of enrolling centers in the United States while preserving the focus on this special patient population. The problem of treating lymphomas in the setting of viral infections is not going away, as has been vividly demonstrated by the ongoing COVID-19 viral pandemic. Treatment regimens, like those used for HIV-associated cancers, will always need to treat both virus and cancer for optimal results.

Conflict-of-interest disclosure: The author declares no competing financial interests.

REFERENCES

REFERENCES
1.
Ramos
JC
,
Sparano
JA
,
Chadburn
A
, et al
.
Impact of Myc in HIV-associated non-Hodgkin lymphomas treated with EPOCH and outcomes with vorinostat (AMC-075 trial)
.
Blood
.
2020
;
136(11):1284-1297
.
2.
Sehn
LH
,
Oestergaard
MZ
,
Trněný
M
, et al
.
Prognostic impact of BCL2 and MYC expression and translocation in untreated DLBCL: results from the phase III GOYA study
.
Hematol Oncol
.
2017
;
35
(
S2
):
131
-
133
.
3.
McPhail
ED
,
Maurer
MJ
,
Macon
WR
, et al
.
Inferior survival in high-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements is not associated with MYC/IG gene rearrangements
.
Haematologica
.
2018
;
103
(
11
):
1899
-
1907
.
4.
Scott
DW
,
King
RL
,
Staiger
AM
, et al
.
High-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements with diffuse large B-cell lymphoma morphology
.
Blood
.
2018
;
131
(
18
):
2060
-
2064
.
5.
Pophali
PA
,
Marinelli
LM
,
Ketterling
RP
, et al
.
High level MYC amplification in B-cell lymphomas: is it a marker of aggressive disease?
Blood Cancer J
.
2020
;
10
(
1
):
5
.
6.
Bartlett
NL
,
Wilson
WH
,
Jung
SH
, et al
.
Dose-adjusted EPOCH-R compared with R-CHOP as frontline therapy for diffuse large B-cell lymphoma: Clinical outcomes of the phase III Intergroup Trial Alliance/CALGB 50303
.
J Clin Oncol
.
2019
;
37
(
21
):
1790
-
1799
.
7.
Wilcox
RA
,
Ristow
K
,
Habermann
TM
, et al
.
The absolute monocyte and lymphocyte prognostic score predicts survival and identifies high-risk patients in diffuse large-B-cell lymphoma
.
Leukemia
.
2011
;
25
(
9
):
1502
-
1509
.
8.
Nowakowski
GS
,
Hong
F
,
Scott
DW
, et al
.
Addition of lenalidomide to R-CHOP (R2CHOP) improves outcomes in newly diagnosed diffuse large B-cell lymphoma (DLBCL): first report of ECOG-ACRIN1412 a randomized phase 2 US Intergroup study of R2CHOP vs R-CHOP
.
Hematol Oncol
.
2019
;
37
(
S2
):
37
-
38
.
9.
Maurer
MJ
,
Ghesquières
H
,
Link
BK
, et al
.
Diagnosis-to-treatment interval is an important clinical factor in newly diagnosed diffuse large B-cell lymphoma and has implication for bias in clinical trials
.
J Clin Oncol
.
2018
;
36
(
16
):
1603
-
1610
.
10.
King
RL
,
Nowakowski
GS
,
Witzig
TE
, et al
.
Rapid, real time pathology review for ECOG/ACRIN 1412: a novel and successful paradigm for future lymphoma clinical trials in the precision medicine era
.
Blood Cancer J
.
2018
;
8
(
3
):
27
.