Combination Targeted Therapy in Relapsed Diffuse Large B-Cell Lymphoma

new england
The
journal of medicine
established in 1812 June 20, 2024 vol. 390 no. 23
Combination Targeted Therapy in Relapsed Diffuse

Large B-Cell Lymphoma
C. Melani, R. Lakhotia, S. Pittaluga, J.D. Phelan, D.W. Huang, G. Wright, J. Simard, J. Muppidi, C.J. Thomas,
M. Ceribelli, F.A. Tosto, Y. Yang, W. Xu, T. Davies‑Hill, S.D. Pack, C.J. Peer, O. Arisa, E. Mena, L. Lindenberg,
E. Bergvall, C.A. Portell, R.J. Farah, S.T. Lee, A. Pradhan, C. Morrison, A. Tadese, A.M. Juanitez, C. Lu, A. Jacob,
H. Simmons, W.D. Figg, S.M. Steinberg, E.S. Jaffe, M. Roschewski, L.M. Staudt, and W.H. Wilson
a bs t r ac t
BACKGROUND
The identification of oncogenic mutations in diffuse large B-cell lymphoma (DLBCL) The authors’ full names, academic de‑
has led to the development of drugs that target essential survival pathways, but grees, and affiliations are listed in the Ap‑
pendix. Dr. Wilson can be contacted at
whether targeting multiple survival pathways may be curative in DLBCL is unknown. wilsonw@mail.nih.gov or at the Lymphoid
Malignancies Branch, Center for Cancer
METHODS Research, National Cancer Institute, Bldg.
We performed a single-center, phase 1b–2 study of a regimen of venetoclax, ibruti- 10, Rm. 4N115, National Institutes of
nib, prednisone, obinutuzumab, and lenalidomide (ViPOR) in relapsed or refrac- Health, Bethesda, MD 20892.
tory DLBCL. In phase 1b, which included patients with DLBCL and indolent lym- Drs. Roschewski, Staudt, and Wilson con‑
phomas, four dose levels of venetoclax were evaluated to identify the recommended tributed equally to this article.
phase 2 dose, with fixed doses of the other four drugs. A phase 2 expansion in This article was updated on June 20, 2024,
patients with germinal-center B-cell (GCB) and non-GCB DLBCL was performed. at NEJM.org.
ViPOR was administered every 21 days for six cycles. N Engl J Med 2024;390:2143-55.
DOI: 10.1056/NEJMoa2401532
RESULTS Copyright © 2024 Massachusetts Medical Society.
In phase 1b of the study, involving 20 patients (10 with DLBCL), a single dose-limiting
toxic effect of grade 3 intracranial hemorrhage occurred, a result that established
venetoclax at a dose of 800 mg as the recommended phase 2 dose. Phase 2 included
40 patients with DLBCL. Toxic effects that were observed among all the patients
included grade 3 or 4 neutropenia (in 24% of the cycles), thrombocytopenia (in 23%),
anemia (in 7%), and febrile neutropenia (in 1%). Objective responses occurred in 54%
of 48 evaluable patients with DLBCL, and complete responses occurred in 38%; com-
plete responses were exclusively in patients with non-GCB DLBCL and high-grade
B-cell lymphoma with rearrangements of MYC and BCL2 or BCL6 (or both). Circulat-
ing tumor DNA was undetectable in 33% of the patients at the end of ViPOR therapy.
With a median follow-up of 40 months, 2-year progression-free survival and overall
survival were 34% (95% confidence interval [CI], 21 to 47) and 36% (95% CI, 23
to 49), respectively.
CONCLUSIONS
Treatment with ViPOR was associated with durable remissions in patients with
specific molecular DLBCL subtypes and was associated with mainly reversible
adverse events. (Funded by the Intramural Research Program of the National Can-
cer Institute and the National Center for Advancing Translational Sciences of the
National Institutes of Health and others; ClinicalTrials.gov number, NCT03223610.)
n engl j med 390;23 nejm.org June 20, 2024 2143

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The n e w e ng l a n d j o u r na l of m e dic i n e
D
iffuse large B-cell lymphoma a fixed duration.21,22 Here, we present the results
(DLBCL) is a molecularly heterogenous of a single-center phase 1b study of venetoclax,
disease for which chemoimmunotherapy ibrutinib, prednisone, obinutuzumab, and lenalid-
can be curative.1-7 Patients with early relapsed or omide (ViPOR) involving patients with relapsed
refractory disease, however, have poor outcomes or refractory B-cell lymphoma and an efficacy
with conventional treatments.8,9 Although anti- analysis for the phase 2 expansion involving pa-
CD19 chimeric antigen receptor (CAR) T-cell tients with relapsed or refractory DLBCL.
therapy has improved outcomes, only approxi-
mately 30 to 40% of patients with relapsed or Me thods
refractory disease are cured with such therapy.10-13
Genetic and functional genomic studies have Patients
revealed oncogenic driver pathways in DLBCL, Patients with relapsed or refractory B-cell lym-
leading to the development of drugs against ac- phoma were eligible for phase 1b, and patients
tionable targets. Although many of these agents with relapsed or refractory DLBCL (including
are active as monotherapy,14-17 they rarely induce high-grade B-cell lymphoma with rearrangements
deep responses or a cure, although certain mo- of MYC and BCL2 or BCL6 [or both] [HGBCL-DH]
lecular subtypes may occasionally and excep- and T-cell histiocyte-rich large B-cell lymphoma)
tionally respond to these agents.18-20 On the basis were eligible for the phase 2 expansion (see the
of previous findings of synergy among targeted Supplementary Methods section in the Supple-
drugs in DLBCL models,21,22 we hypothesized mentary Appendix, available with the full text of
that inhibiting multiple survival pathways simul- this article at NEJM.org). Patients 18 years of age
taneously could be curative in certain DLBCL or older with an Eastern Cooperative Oncology
molecular subtypes. Group performance-status score of 2 or less (on a
Survival pathways in the activated B-cell (ABC) scale of 0 to 5, with higher numbers reflecting
subtype of DLBCL include chronic active B-cell greater disability) and adequate organ function
receptor (BCR) signaling to activate the nuclear (unless secondary to lymphoma) were eligible.
factor κB (NF-κB) and phosphoinositide 3-kinase Patients with DLBCL had to have undergone previ-
(PI3K), prevention of apoptosis by B-cell lym- ous anthracycline therapy, and all the patients had
phoma 2 (BCL2), and expression of the lineage- to have previously received anti-CD20 antibodies.
restricted transcription factors interferon regu- Key exclusion criteria were active central ner-
latory factor 4 (IRF4), Ikaros, and Aiolos.23,24 In vous system disease, current pregnancy or breast-
the germinal-center B-cell (GCB) subtype of feeding, the use of strong inducers or inhibitors
DLBCL, cell viability is maintained by constitutive of cytochrome P-450 3A4 (CYP3A4), and human
BCR-dependent PI3K signaling, BCL2, Ikaros, and immunodeficiency virus infection. Previous treat-
Aiolos.25,26 These survival pathways can be blocked ment with venetoclax, ibrutinib, or lenalidomide
by targeted drugs, including the Bruton’s tyro- was allowed. The study was approved by the Na-
sine kinase inhibitor ibrutinib, which targets tional Cancer Institute institutional review board,
BCR-dependent NF-κB activation; glucocorticoids, and all the patients provided written informed
which target proximal BCR signaling27; the BCL2 consent in accordance with the Declaration of
inhibitor venetoclax; and lenalidomide, which Helsinki (see the protocol, available at NEJM.org).
targets Ikaros, Aiolos, and indirectly IRF4. Pre- The authors vouch for the completeness and ac-
clinical studies have shown synergistic killing curacy of the data and for the fidelity of the study
of DLBCL cell lines by combinations of these to the protocol.
drugs.21,22
We developed a regimen that used four drugs Treatment
— venetoclax, ibrutinib, prednisone, and lenalid- In phase 1b, we used a 3+3 design to determine
omide — to target these pathways and included the recommended dose of venetoclax for phase
obinutuzumab to trigger innate immune re- 2 as assessed across four different dose levels
sponses to malignant B cells (Fig. 1A). To maxi- — 200 mg (dose level 1), 400 mg (dose level 2),
mize potential synergy while minimizing the 600 mg (dose level 3), and 800 mg (dose level 4) on
cumulative drug-related toxic effects, we admin- days 2 to 14 (patients treated at dose level 1 in the
istered all the agents in noncontinuous cycles for phase 1b cohort began venetoclax on cycle 2)
2144 n engl j med 390;23 nejm.org June 20, 2024

Combination Ther apy in Diffuse Large B-Cell Lymphoma
(Table S1 in the Supplementary Appendix). Venet- overall response. Response duration, progression-
oclax was administered in combination with free survival, and overall survival were deter-
ibrutinib at a fixed dose of 560 mg on days 1 to mined with the use of the Kaplan–Meier method,
14, prednisone at a dose of 100 mg on days 1 to 7, with the median and 95% confidence interval
obinutuzumab at a dose of 1000 mg on days 1 reported for each analysis and with a data-cutoff
to 2, and lenalidomide at a dose of 15 mg on date of July 11, 2023. Response duration was cal-
days 1 to 14 (Fig. 1B). All the patients had a 12- culated in all patients who had a response from
day initial ramp-up to the target dose level of the date of the first response to the date of re-
venetoclax (Table S2) and received allopurinol as lapse or progression or the date of the last follow-
prophylaxis for tumor lysis syndrome, with se- up. Progression-free and overall survival were cal-
rial laboratory monitoring for tumor lysis syn- culated for all the patients with DLBCL from the
drome in patients according to their pretreat- date of study enrollment to the date of relapse or
ment risk (tumor bulk as shown on computed progression, death, or the last follow-up, as ap-
tomography [CT]). Details of the laboratory mon- propriate. PET and minimal residual disease
itoring for tumor lysis syndrome and the criteria analyses performed on the basis of data obtained
for dose-limiting toxic effects are provided in after cycles 1 or 2 or at the end of therapy were
the Supplementary Methods section. calculated as beginning at the time the data were
The phase 2 expansion cohorts, made up of 20 obtained. Additional statistical methods are de-
patients with GCB and 20 patients with non-GCB scribed in the Supplementary Appendix.
DLBCL, were assessed at the recommended phase
2 dose. ViPOR was administered every 21 days for R e sult s
six cycles unless disease progression or unaccept-
able toxic effects occurred. All the patients received Patients
growth factor support and Pneumocystis jirovecii We enrolled 60 patients with relapsed or refrac-
prophylaxis, with venous thromboembolism pro- tory B-cell lymphoma from February 2018 through
phylaxis administered if indicated. Pretreatment June 2021, including 20 patients (10 with DLBCL)
biopsy specimens were analyzed with the use of in phase 1b and 40 patients (all with DLBCL) in
whole-exome and transcriptome sequencing. Base- phase 2 (Table 1). Among the 50 patients with
line CT, 18F-fluorodeoxyglucose–positron-emission DLBCL, the median age was 61 years (range, 29
tomography (FDG-PET), and bone marrow aspira- to 77), 92% had stage III or IV disease, 86% had
tion and biopsy were performed, with restaging elevated levels of lactate dehydrogenase, 56%
CT and PET scans performed during treatment had at least two extranodal sites of disease, and
and follow-up (Fig. 1B). Plasma samples were col- 68% had a score of 3 or higher on the Interna-
lected for circulating-tumor DNA (ctDNA) analy- tional Prognostic Index (range, 0 to 5, with higher
sis with the use of clonoSEQ (Fig. 1B),28 as well scores indicating a worse prognosis). A total of
as for pharmacokinetic analyses (see the Sup- 17 patients with DLBCL (34%) had transformed
plementary Methods for details of prophylaxis, lymphoma. The median number of previous
analyses, and imaging). Response to therapy was systemic therapies was 3 (range, 1 to 9), includ-
classified with the use of the Lugano criteria.29 ing in 20 patients (40%) who had received pre-
vious CAR T-cell therapy and 29 (58%) with
Statistical Analysis refractory disease as classified with the use of
In phase 1b, a maximum of 30 patients could be criteria from the retrospective SCHOLAR-1
treated to assess the four dose levels of veneto- study.9 A total of 25 patients had DLBCL not
clax and allow for a potential fifth dose level otherwise specified, including 12 with GCB
(dose level −1). In phase 2, an additional 40 pa- subtypes and 13 with non-GCB subtypes
tients with relapsed or refractory DLBCL were grouped according to immunohistochemical
treated at the recommended phase 2 dose. We analysis.30,31 Twenty patients had HGBCL-DH,
calculated that with a sample size of 40 patients including 17 with MYC and BCL2 translocations
with relapsed or refractory disease, an exact bi- (HGBCL-DH-BCL2) and 3 with MYC and BCL6
nomial test with a one-sided significance level translocations (HGBCL-DH-BCL6), and 5 patients
of 0.10 would provide the study with 87% power had T-cell histiocyte-rich large B-cell lymphoma
to rule out a response of 40% and target a 60% (Tables 1 and S3).31

A Targeted Survival Pathways B Treatment and Follow-up

B-cell
CD20 receptor ViPOR
Obinutuzumab
Obinutuzumab
Prednisone
B CELL Prednisone Ibrutinib
Lenalidomide
Ibrutinib BTK
Venetoclax Venetoclax
1 2 3 4 5 6 7 8 9 10 11 12 13 14 21
BCL2 Days
Treatment Follow-up
Mitochondria NF-κB
ViPOR,
6 cycles Yr 1 Yr 2 Yr 3 Yr 4 Yr 5
Every 3 mo Every 4 mo Every 6 mo Every 12 mo
Lenalidomide IRF4
Prednisone GR IKZF1 IKZF3

PET scans CT scans ctDNA analysis Genomic analysis (WES, RNA-seq)
C Change in Lesion Sum of the Product of the Diameters (SPD) after ViPOR Therapy
140
60
50
40
Percent Change in SPD from Baseline
30
20
Refractory
10 (SCHOLAR-1 criteria)
0 Previous CAR T-cell
−10 Treatment
Complete Response
−20
by FDG-PET
−30
−40
−50 PR
−60
−70
−80
−90
−100
GCB DLBCL NOS Non-GCB DLBCL NOS HGBCL-DH-BCL2 HGBCL- THRLBCL
DH-BCL6
Molecular Subtypes
COO (IHC) GCB Non-GCB
COO (RNA) GCB Unclassified

ABC NA
LymphGen MCD BN2 A53

EZB-MYC+ N1
VP-85
VP-23
VP-45
VP-03
VP-25
VP-21
VP-33
VP-65
VP-43
VP-71
VP-13
VP-63
VP-55
VP-41
VP-42
VP-44
VP-22
VP-24
VP-02
VP-19
VP-49
VP-08
VP-07
VP-59
VP-26
VP-78
VP-54
VP-79
VP-29
VP-27
VP-67
VP-82
VP-38
VP-69
VP-76
VP-06
VP-64
VP-48
VP-32
VP-18
VP-74
VP-56
VP-66
VP-36
VP-80
VP-50
VP-10
VP-70
Study No.
EZB-MYC− Other
Composite
Toxic Effects and Pharmacokinetics ing to disease progression). One of the 18 evalu-
In phase 1b, 18 of the 20 patients were evaluable able patients had a dose-limiting toxic effect of
for dose-limiting toxic effects (2 patients were grade 3 intracranial hemorrhage at dose level 1
not evaluable for dose-limiting toxic effects ow- in the context of concomitant treatment with

Figure 1 (facing page). ViPOR Treatment Regimen. despite continued treatment. Serious adverse events
Panel A shows the survival pathways targeted by the occurred in 42% of the patients (Tables S7 and S8),
ViPOR (venetoclax, ibrutinib, prednisone, obinutuzumab, with non-neutropenic fever the most common
and lenalidomide) regimen. The doses of ViPOR agents serious adverse event.
and the schedule of post-treatment surveillance moni‑ Dose reductions and delays owing to toxic
toring are shown in Panel B. Obinutuzumab was ad‑
effects occurred in 17% and 25% of the patients,
ministered intravenously at a dose of 1000 mg daily;
prednisone (100 mg), ibrutinib (560 mg), lenalidomide respectively, and five patients prematurely dis-
(15 mg), and venetoclax (800 mg) were administered continued the study intervention owing to an
orally once daily. A waterfall plot in Panel C depicts the unacceptable adverse event or intercurrent ill-
percent change in the sum of the product of the diam‑ ness (see the Supplementary Results section).
eters of measurable lesions as assessed with computed
Results of pharmacokinetic analyses of veneto-
tomography. Immunohistochemical (IHC) and RNA
sequencing of tumor samples were analyzed to identi‑ clax, ibrutinib, and lenalidomide were compa-
fy diffuse large B-cell lymphoma (DLBCL) cell-of-origin rable to published single-agent data, indicating
subtypes, and genetic subtypes were assigned with the no clinically significant drug interactions (Fig. S2
use of the LymphGen algorithm. ABC denotes activated and Table S9).32-34
B-cell, BTK Bruton’s tyrosine kinase, CAR chimeric anti‑
gen receptor, ctDNA circulating-tumor DNA, FDG-PET
18
F-fluorodeoxyglucose–positron-emission tomogra‑
Clinical Outcomes
phy, GCB germinal-center B cell, HGBCL-DH-BCL2 A total of 48 patients with DLBCL were evaluable
high-grade B-cell lymphoma with MYC and BCL2 rear‑ for a response (2 patients with HGBCL-DH-BCL2
rangements, HGBCL-DH-BCL6 high-grade B-cell lympho‑ discontinued therapy owing to toxic effects be-
ma with MYC and BCL6 rearrangements, IHC immuno‑
fore restaging). Responses were seen in 54% of
histochemical analysis, IKZF1 Ikaros, IKZF3 Aiolos,
IRF4 interferon regulatory factor 4, NF-κB nuclear factor the patients (26 patients), with 38% (18 patients)
κB, and THRLBCL T-cell histiocyte-rich large B-cell having a complete response (Fig. 1C and Table 2).
lymphoma. The median time to response was 0.66 months
(range, 0.59 to 4.34), with 78% of complete re-
sponses durable and without consolidation (see
enoxaparin and aspirin. No other dose-limiting the Supplementary Results). Complete responses
toxic effects occurred, and venetoclax 800 mg were observed in 62% of patients (8 of 13) with
was identified as the recommended phase 2 dose. non-GCB DLBCL not otherwise specified, 53% of
Hematologic adverse events of any grade oc- patients (8 of 15) with HGBCL-DH-BCL2, 33% of
curred in more than two thirds of the patients patients (1 of 3) with HGBCL-DH-BCL6, and 20%
(Fig. 2), with grade 3 or 4 neutropenia, throm- of patients (1 of 5) with T-cell histiocyte-rich
bocytopenia, and anemia observed in 24%, 23%, large B-cell lymphoma. Among 12 patients with
and 7% of cycles, respectively (Tables S4 and S5). GCB DLBCL not otherwise specified, no patients
In addition, only three episodes of grade 3 fe- had complete responses and 33% (4 patients) had
brile neutropenia occurred, and subsets of the partial responses (Table 2).
levels of T-cell lymphocytes were generally unaf- With a median follow-up of 40 months (inter-
fected after therapy (Fig. S1, Table S6, and Sup- quartile range, 32 to 51), 2-year progression-free
plementary Results). survival was 34% (95% confidence interval [CI],
Although hypokalemia was the only nonhe- 21 to 47) in all patients with DLBCL (Fig. 3A). In
matologic grade 3 or 4 adverse event observed in patients with a response, 2-year response duration
10% or more of the patients (observed in 28%), was 65% overall, including 78% of patients with
67% of the patients had hypokalemia of any complete responses and 38% of patients with par-
grade that resulted in electrolyte replacement. tial responses to ViPOR (Fig. S3 and Fig. 3B). Re-
Other nonhematologic adverse events included sults of analysis according to subtype showed that
diarrhea (in 68% of the patients), nausea (in 2-year progression-free survival was 39% with non-
45%), rash (in 35%), and fatigue (in 33%) GCB DLBCL not otherwise specified, 47% with
(Fig. 2). Grade 3 atrial fibrillation occurred in HGBCL-DH-BCL2, 33% with HGBCL-DH-BCL6,
three patients, and one major hemorrhagic event 40% with T-cell histiocyte-rich large B-cell lym-
occurred. One grade 4 tumor lysis syndrome phoma, and 8% with GCB DLBCL not otherwise
event occurred, was resolved, and did not recur specified (Fig. 3C). Overall survival largely re-

Table 1. Characteristics of the Patients at Baseline.*
Dose Levels 1–4, DLBCL, Total

Phase 1b Phase 2 DLBCL Total
Characteristic (N = 20) (N = 40) (N = 50) (N = 60)
Median age (range) — yr 58 (34–76) 59 (29–77) 61 (29–77) 58 (29–77)
Male sex — no. (%) 13 (65) 26 (65) 33 (66) 39 (65)
Race or ethnic group — no. (%)†
White 15 (75) 25 (62) 33 (66) 40 (67)
Black 3 (15) 10 (25) 11 (22) 13 (22)
Asian 2 (10) 1 (2) 2 (4) 3 (5)
Hispanic 0 4 (10) 4 (8) 4 (7)
Histologic type — no. (%)
Non-GCB DLBCL NOS 4 (20) 9 (22) 13 (26) 13 (22)
HGBCL-DH-BCL6 0 3 (8) 3 (6) 3 (5)
THRLBCL 0 5 (12) 5 (10) 5 (8)
GCB DLBCL NOS 4 (20) 8 (20) 12 (24) 12 (20)
HGBCL-DH-BCL2 2 (10) 15 (38) 17 (34) 17 (28)
Follicular lymphoma 8 (40) 0 0 8 (13)
Marginal-zone lymphoma 2 (10) 0 0 2 (3)
Transformed lymphoma — no./total no 4/10 (40) 13/40 (32) 17/50 (34) —
(%)‡§
ECOG score ≥2 — no. (%)¶ 3 (15) 4 (10) 7 (14) 7 (12)
Stage III or IV disease — no. (%) 18 (90) 37 (92) 46 (92) 55 (92)
Elevated LDH level — no. (%) 13 (65) 35 (88) 43 (86) 48 (80)
Two or more extranodal sites — no. (%) 12 (60) 22 (55) 28 (56) 34 (57)
IPI score ≥3 — no./total no. (%)‡‖ 7/10 (70) 27/40 (68) 34/50 (68) —
Median no. of previous therapies (range) 3 (1–7) 3 (1–9) 3 (1–9) 3 (1–9)
Previous therapies — no. (%)
One study agent** 6 (30) 14 (35) 18 (36) 20 (33)
ASCT 4 (20) 3 (8) 5 (10) 7 (12)
Allo-HSCT 1 (5) 0 1 (2) 1 (2)
CAR T-cell 3 (15) 17 (42) 20 (40) 20 (33)
Refractory status††
Primary refractory — no. (%) 9 (45) 27 (68) 30 (60) 36 (60)
Refractory — no./total no. (%)‡ 6/10 (60) 23/40 (58) 29/50 (58) —
* Allo-HSCT denotes allogeneic hematopoietic stem-cell transplantation, ASCT autologous stem-cell transplantation,
CAR chimeric antigen receptor, DLBCL diffuse large B-cell lymphoma, GCB DLBCL germinal-center B-cell diffuse large
B-cell lymphoma, HGBCL-DH-BCL2 high-grade B-cell lymphoma with MYC and BCL2 rearrangements, HGBCL-DH-BCL6
high-grade B-cell lymphoma with MYC and BCL6 rearrangements, LDH lactate dehydrogenase, non-GCB DLBCL non–
germinal-center B-cell diffuse large B-cell lymphoma, NOS not otherwise specified, and THRLBCL T-cell histiocyte-rich
large B-cell lymphoma.
† Race and ethnic group were reported by the patients.
‡ This category includes 50 patients with aggressive B-cell lymphoma. The total number for dose levels 1 through 4 repre‑
sents 10 patients with DLBCL in phase 1b.
§ Transformed lymphoma totals include 17 patients with transformed DLBCL from an underlying indolent lymphoma,
15 with transformed DLBCL from follicular lymphoma, and 2 with transformed DLBCL from marginal-zone lymphoma,
including 9 with DLBCL that transformed to HGBCL-DH-BCL2, 5 with DLBCL that transformed to GCB DLBCL NOS,
and 3 with DLBCL that transformed to non-GCB DLBCL NOS.
¶ Scores on the Eastern Cooperative Oncology Group (ECOG) performance-status scale range from 0 to 5, with higher
numbers reflecting greater disability.
‖ Scores on the International Prognostic Index (IPI) range from 0 to 5, with higher scores indicating a worse prognosis.
** This category includes 12 patients who previously received lenalidomide, 7 patients who previously received ibrutinib
or acalabrutinib, and 1 patient who previously received venetoclax.
†† Primary refractory status was defined as less than a complete response to first-line chemoimmunotherapy. Refractory
status was determined on the basis of the SCHOLAR-1 criteria.9

flected progression-free survival both overall a paired scan at the end of therapy (Table S10 and
and among different DLBCL subtypes (Fig. S4). Supplementary Results). Patients with a Deau-
Patients with DLBCL who received ViPOR as ville score of 5 at the end of therapy had shorter
second-line therapy had greater progression-free progression-free survival (log-rank hazard ratio,
survival than patients who received ViPOR as 4.58 [95% CI, 2.07 to 10.15]) and lower overall
third-line or later therapy (log-rank hazard ratio,
survival (log-rank hazard ratio, 5.39 [95% CI,
0.33; 95% CI, 0.17 to 0.66) (Table 2 and Fig. S5).
2.33 to 12.45]) than patients with a Deauville
Four patients had relapse of systemic disease score of 1–4 (Supplementary Results). In addi-
after having a complete response, all within 18 tion, patients with an elevated total metabolic
months of treatment, and one patient died of tumor volume or total lesion glycolysis levels
coronavirus disease 2019 while in remission 31 that were above the median at baseline were less
months after treatment with ViPOR (Fig. S6). likely to have a complete response than patients
Response and survival data for additional sub- whose levels were below the baseline median,
sets of DLBCL, including transformed, post–CAR and they also had shorter progression-free sur-
T-cell therapy, refractory, and molecular DLBCL vival and lower overall survival (Figs. S8 and S9).
subtypes, are shown in Table 2, Fig. S7, and the Of the patients with DLBCL, 90% (45 pa-
Supplementary Results section. tients) had detectable ctDNA levels at baseline
available for analysis of minimal residual dis-
PET Imaging and Minimal Residual Disease ease (Table S11 and Supplementary Results).
Baseline PET images were available for all 50 After patients received ViPOR, the ctDNA con-
patients with DLBCL, with 41 patients having had centration levels decreased rapidly, with 33% of
Toxic Effects
Grade 1 or 2 Grade 3 Grade 4
Thrombocytopenia 45 30 15
Anemia 48 25
Neutropenia 18 22 30
Diarrhea 60 8
Hypokalemia 38 27 2
Nausea 45
Rash 35
Fatigue 30 3
Hypophosphatemia 32
Hypomagnesemia 32
Vomiting 30 2
Constipation 27
Hypocalcemia 25
Increased Creatinine Level 22
Increased ALT Level 17 22
0 10 20 30 40 50 60 70 80 90 100
Percentage of Patients
Figure 2. Adverse Events.

Adverse events that were judged to be at least possibly related to ViPOR therapy and occurring in 20% or more of
the patients are shown in descending order of incidence. ALT denotes alanine aminotransferase.

Table 2. Response and Survival.
Progression-free Overall Survival

Variable Overall Response Complete Response Survival at 2 yr at 2 yr
no./total no. (%) % (95% CI)

All DLBCL 26/48 (54) 18/48 (38) 34 (21–47) 36 (23–49)
Histologic type
Non-GCB DLBCL NOS 8/13 (62) 8/13 (62) 39 (14–63) 39 (14–63)
HGBCL-DH-BCL6 1/3 (33) 1/3 (33) 33 (1–77) 33 (1–77)
THRLBCL 3/5 (60) 1/5 (20) 40 (5–75) 40 (5–75)
GCB DLBCL NOS 4/12 (33) 0/12 (0) 8 (1–31) 17 (3–41)
HGBCL-DH-BCL2 10/15 (67) 8/15 (53) 47 (23–68) 47 (23–68)
Line of therapy
Second-line therapy 12/15 (80) 11/15 (73) 60 (32–80) 60 (32–80)
Third-line therapy or later 14/33 (42) 7/33 (21) 23 (11–38) 25 (13–41)
Transformed lymphoma 7/15 (47) 5/15 (33) 29 (11–51) 28 (10–51)
Previous CAR T-cell therapy 9/20 (45) 4/20 (20) 30 (12–50) 30 (12–50)
Refractory disease* 12/27 (44) 5/27 (19) 21 (8–37) 24 (11–41)
* Refractory disease was determined according to criteria from the SCHOLAR-1 study.9
all the patients and 93% of those with a PET- tion of prednisolone (the active metabolite of pred-
confirmed complete response having undetect- nisone) with venetoclax was synergistically toxic in
able ctDNA at the end of therapy (Fig. S10). An two of the four ABC models, but prednisolone plus
elevated baseline ctDNA concentration of 2.5 lenalidomide was synergistic in a different pair of
log10 haploid genome equivalents per milliliter models, and prednisolone plus ibrutinib was syn-
was associated with shorter progression-free ergistic in all four models (Fig. S15). In addition,
survival and lower overall survival, whereas un- this result was in contrast to the lack of synergistic
detectable levels of ctDNA after cycle 1 or cycle cytotoxicity observed in most GCB cell-line models
2 or at the end of therapy were associated with (Fig. S16). Using a quantitative measure of apopto-
longer progression-free survival and greater over- sis, we tested each ViPOR drug individually and as
all survival than with detectable levels of ctDNA a four-drug combination over a 2–to–24-hour time
(Figs. S11 and S12). Of 15 patients who had a period. In two ABC models, the four-drug combi-
complete response as shown on serial ctDNA nation produced more rapid and profound apop-
samples, 11 remained progression-free with un- tosis than any individual ViPOR agent (Fig. 4A).
detectable ctDNA, whereas of 4 patients who had Thus, although individual DLBCL models re-
relapse, 3 had a molecular relapse before clinical sponded differentially to ViPOR drug doublets,
relapse was seen on imaging (Fig. S13). the combination of all four ViPOR drugs over-
came this functional heterogeneity.
Mechanistic Foundation of ViPOR Efficacy We analyzed whole-exome and RNA sequenc-
To explore the basis for ViPOR sensitivity, we ing of ViPOR tumor samples to assign tumors to
used high-throughput drug screens to measure DLBCL genetic subtypes using the LymphGen
the cytotoxicity of the four small-molecule ViPOR algorithm3 and to cell-of-origin gene expression
drugs in pairwise dose–response titrations in subtypes (Figs. S17 and S18). The percentage of
ABC cell-line models and used the ΔBliss metric patients with a complete response was consider-
to quantify drug synergy (Fig. S14).21 Although ably higher among those with the MCD subtype
synergistic cytotoxicity was observed with all the (six patients [83%]; 95% CI, 53 to 100) than
drug doublets, the pattern of synergy varied among patients with all other genetically classi-
across ABC models. For example, the combina- fied DLBCL subtypes (22%; 95% CI, 3 to 41) and

Figure 3. Progression-free Survival. A Progression-free Survival among All Patients with DLBCL
Panel A shows the Kaplan–Meier curve for progres‑ 100
sion-free survival starting at the on-study date for all 90
the patients with DLBCL. One patient with non-GCB 80
DLBCL not otherwise specified died of coronavirus dis‑ 70
ease 2019 while in remission at 31 months after com‑
60
pletion of ViPOR therapy. Panel B shows a Kaplan–
50
Meier analysis of the duration of response starting at
the response date and stratified according to a com‑ 40
plete or partial response to treatment with ViPOR. Two 30
patients (one who had a complete response and one 20
who had a partial response) died without disease re‑ 10
lapse or progression, and their data were censored at 0
the time of death. Panel C shows the Kaplan–Meier 0 6 12 18 24 30 36 42 48 54
analysis for progression-free survival starting at the Months
on-study date and stratified according to the histologic
DLBCL subtype. No. at Risk 50 25 20 18 16 13 8 4 4
B Duration of Response to ViPOR

100
in all patients with non-MCD subtypes (32%; 90
95% CI, 22 to 42) (Fig. 4B). In addition, the one 80
Complete response
patient with N1 DLBCL also had a complete re- 70
sponse. With regard to the gene-expression 60
subtypes, the percentage of patients with a com- 50
plete response was greatest among those with 40
the ABC subtype (8 of 14 patients [57%]) and 30 Partial response
those with an unclassified DLBCL subtype (3 of 20

8 patients [38%]), and was lowest among those 10
with the GCB DLBCL subtype (6 of 22 patients 0
0 6 12 18 24 30 36 42 48 54
[27%]). Together, these data support the hypoth-
Months
esis that the MCD and possibly N1 genetic sub-
No. at Risk
types of ABC DLBCL probably benefited from Complete response 18 18 16 15 13 8 5 3 2
ViPOR owing to the exceptional reliance of these Partial response 8 5 4 3 2 2 2 2 2
subtypes on BCR-dependent NF-κB activation.18,19
A high percentage of patients with HGBCL-DH- C Progression-free Survival According to Subtype
100
BCL2 had a durable complete response after re-
90
ceiving ViPOR. HGBCL-DH-BCL2 tumors are
80
classified as EZB-MYC+ subtypes in the DLBCL
70
genetic taxonomy, whereas other GCB DLBCLs
60
are classified as EZB-MYC–, ST2, and BN2 sub- 50 HGBCL-DH-BCL2
types (Fig. S19).3 A complete response was seen 40 THRLBCL
in more patients with the EZB-MYC+ subtype (3 30 HGBCL-DH-BCL6
of 6 patients [50%]) than with the EZB-MYC– 20
Non-GCB DLBCL NOS
subtype (0 of 6 patients), suggesting that the 10
dual translocations of MYC and BCL2 might con- 0
GCB DLBCL NOS
fer sensitivity to ViPOR (Fig. 4B). To test this 0 6 12 18 24 30 36 42 48 54
hypothesis, we measured the cytotoxicity of the Months

four ViPOR agents in 12 GCB DLBCL cell-line No. at Risk
GCB DLBCL NOS 12 4 3 2 2 2 2 2 2
models: EZB-MYC+ (5 cell lines), EZB-MYC– (4 Non-GCB DLBCL 13 10 7 6 6 6 4 2 2
cell lines), ST2 (2 cell lines), and genetically un- NOS
HGBCL-DH-BCL2 17 10 9 9 8 5 3 2 2
classified GCB (1 cell line). The EZB-MYC+ cell HGBCL-DH-BCL6 3 2 2 2 2 2 0 0 0
lines were strikingly more sensitive to venetoclax THRLBCL 5 3 3 3 2 2 2 0 0
than the EZB-MYC– or other GCB models. This

difference in sensitivity of GCB genetic subtypes Discussion

was not observed with the other ViPOR agents.
This finding suggests that BCL2 inhibition with In this study, we found evidence that the simul-
venetoclax probably contributes prominently to taneous targeting of multiple survival pathways
the percentage of patients with EZB-MYC+ DLBCL is potentially curative in specific molecular sub-
who had a durable complete response to ViPOR. types of DLBCL. To optimize multiagent drug
A Apoptosis
HBL1 OCI-Ly10
(ABC DLBCL) (ABC DLBCL)
30,000 15,000 Venetoclax+
Apoptosis (Caspase 3/7 Glo RLU)
ibrutinib+
25,000 12,500 prednisone
(prednisolone)+
20,000 10,000 lenalidomide
Venetoclax
15,000 7,500
(200 nmol/liter)
10,000 5,000 Ibrutinib
(200 nmol/liter)
5,000 2,500 Prednisone
(prednisolone)
0 0 (500 nmol/liter)
Lenalidomide
−5,000 −2,500 (500 nmol/liter)
0 2 4 6 8 10 12 14 16 18 20 22 24 0 2 4 6 8 10 12 14 16 18 20 22 24
Treatment (hr)
B Response
DLBCL Genetic Subtype DLBCL Gene-Expression Subtypes
1/1
100 100
90 90
Percentage with Complete Response
5/6
80 80
70 70
60 60 8/14
3/6
50 50
40 40 3/8
30 30 6/22
20 20
10 10
0/3 0/2 0/6
0 0
MCD N1 A53 BN2 EZB- EZB- ABC Unclassified GCB
MYC− MYC+
Complete response Partial response Stable disease Progressive disease
Figure 4. Molecular Correlates of ViPOR Response.

Panel A shows the relative luminescence units (RLU) for cleaved caspase 3 and caspase 7 (as measured with the use of Caspase-Glo) in
the indicated ABC DLBCL cell lines in culture with ViPOR agents singly or in combination for 2 to 24 hours. Panel B shows complete re‑
sponse in patients treated with ViPOR, as measured by tumor biopsy, grouped according to LymphGen genetic subtype (left) or cell-of-
origin gene expression–assigned subtype (right). Pie charts are scaled to the total number of biopsy specimens in which each subtype
was detected and display the percentage of patients with a complete response, a partial response, stable disease, or progressive disease.

synergy, we designed a schedule reminiscent of (HGBCL-DH-BCL2), with a higher 2-year progres-

combination chemotherapy, in which all target- sion-free survival among patients with those tu-
ed agents were concurrently administered in a mors than among patients with GCB tumors that
noncontinuous fashion for a maximum of six lacked both translocations (47% vs. 8%). Mecha-
cycles. This strategy avoided the cumulative nistically, MYC can sensitize cells to apoptosis, but
toxic effects that are associated with continuous BCL2 can block this toxic effect.39 Venetoclax had
or indefinite drug dosing and thereby allowed greater toxic effects in cell-line models of HGBCL-
the safe administration of multiple targeted DH-BCL2 than in other GCB DLBCL lines, leading
agents. Although hematologic toxic effects were us to speculate that the inclusion of venetoclax in
common and occurred in more than two thirds ViPOR may expose HGBCL-DH-BCL2 tumors to
of the patients, serious hematologic adverse the toxic effects of MYC.
events occurred in less than a quarter of the Among patients who had previously under-
cycles, with febrile neutropenia observed in only gone CAR T-cell therapy, ViPOR was associated
1% of the cycles. Intermittent drug dosing also with 2-year progression-free survival in 30%,
resulted in fewer nonhematologic toxic effects, suggesting the treatment may alter the poor
such as high-grade rash, than had been seen in prognosis in these patients.40 Additionally, ViPOR
continuous targeted-therapy regimens.35-37 De- allowed successful bridging to radiotherapy,
spite an initial concern about possible tumor CAR T-cell therapy, or allogeneic transplanta-
lysis syndrome and hyperkalemia occurring in tion in more than one third of the patients who
patients who received ViPOR, diarrhea and hy- had a partial response. With a median follow-up
pokalemia were more commonly observed than of 40 months, more than one third of all patients
tumor lysis syndrome and hyperkalemia, with with DLBCL were progression-free at 2 years, with
most patients receiving antidiarrheal medication 78% of the complete responses being durable
and electrolyte support, in contrast to the one responses without consolidation. Not unexpect-
event of tumor lysis syndrome that was observed. edly, ViPOR led to higher percentages of complete
In addition, adverse events frequently resolved responses and progression-free survival when
during the off-treatment week, and most patients administered as second-line therapy, suggesting it
received all treatment cycles on schedule and with- should be considered early in the treatment of
out dose reductions. patients with relapsed or refractory DLBCL.
Owing to the molecular heterogeneity and PET and molecular biomarkers of disease were
complex aberrant genetic landscape of DLBCL, prognostic of outcome after treatment with ViPOR.
we hypothesized that the inhibition of multiple An elevated baseline metabolic (i.e., TMTV and
driver pathways is necessary for the curative TLG) or molecular (i.e., ctDNA) disease burden
potential of targeted therapy. ViPOR synergisti- was associated with inferior progression-free and
cally targets key survival pathways in non-GCB overall survival. During therapy, ctDNA provided
DLBCL, including BCR-dependent NF-κB signal- an early predictor of long-term outcome, as did
ing with the combination of ibrutinib, lenalido- undetectable ctDNA at the end of therapy.
mide, and prednisone,21-23,27 as well as the apop- Our study has several strengths. We showed
tosis pathway with the BCL2 inhibitor venetoclax. that multiple targeted agents could be concur-
In line with this hypothesis, ViPOR was associ- rently administered safely and with an accept-
ated with greater percentages of patients with a able side-effect profile in adult patients of all
complete response (62%) and 2-year progres- ages with relapsed or refractory DLBCL. Our
sion-free survival (39%) in non-GCB DLBCL than study also showed that simultaneous targeting
in GCB DLBCL not otherwise specified. Of note, of multiple survival pathways is potentially cura-
more patients with MCD DLBCL had a complete tive in specific molecular subtypes of relapsed or
response (83%) than patients with other genetic refractory DLBCL. ViPOR was not curative in
DLBCL subtypes, a finding that aligns with pre- GCB DLBCL not otherwise specified, highlight-
vious laboratory and clinical evidence of excep- ing the need to develop and test agents targeting
tional dependence of MCD tumors on BCR sig- GCB-specific pathways. Of note, durable com-
naling.15,19,20,24,38 plete responses were observed in the patients
Unexpectedly, ViPOR was highly active in who were heavily pretreated with chemotherapy
GCB tumors with MYC and BCL2 translocations or CAR T-cell therapy.

As with any phase 2 study, one must recog- Meeting of the American Society of Hematology, San Diego,
California, December 5–8, 2020; and the 65th Annual Meeting
nize the limitations related to sample size and of the American Society of Hematology, San Diego, California,
patient selection. Although the efficacy of December 9–12, 2023.
ViPOR in specific molecular subtypes limited Supported by the Intramural Research Program of the Na-
tional Cancer Institute and the National Center for Advancing
the subgroup of patients with DLBCL who had Translational Sciences of the National Institutes of Health.
potentially curable disease, this very specificity Genentech provided venetoclax and obinutuzumab and Bristol
provides some confidence in the generalizability Myers Squibb–Celgene provided lenalidomide under clinical
trial agreements with the National Cancer Institute, and the
of our results. The activity of ViPOR in patients National Institutes of Health Clinical Center Pharmacy Depart-
with relapsed or refractory non-GCB DLBCL and ment provided ibrutinib and prednisone.
HGBCL-DH-BCL2 is a topic for future study. Disclosure forms provided by the authors are available with
the full text of this article at NEJM.org.
Presented in part at the 15th International Conference on A data sharing statement provided by the authors is available
Malignant Lymphoma, Lugano, Switzerland, June 18–22, 2019; with the full text of this article at NEJM.org.
the 61st Annual Meeting of the American Society of Hematol- We thank Lindsay Barrow for technical assistance in replicat-
ogy, Orlando, Florida, December 7–10, 2019; the 62nd Annual ing the original data for cell-viability experiments.
Appendix
The authors’ full names and academic degrees are as follows: Christopher Melani, M.D., Rahul Lakhotia, M.B., B.S., Stefania Pittaluga,
M.D., Ph.D., James D. Phelan, Ph.D., Da Wei Huang, M.D., George Wright, Ph.D., Jillian Simard, M.D., Jagan Muppidi, M.D., Ph.D.,
Craig J. Thomas, Ph.D., Michele Ceribelli, Ph.D., Frances A. Tosto, M.S., Yandan Yang, Ph.D., Weihong Xu, M.S., Theresa Davies‑Hill,
B.S., Svetlana D. Pack, Ph.D., Cody J. Peer, Ph.D., Oluwatobi Arisa, Ph.D., Esther Mena, M.D., Liza Lindenberg, M.D., Ethan Bergvall,
M.D., Craig A. Portell, M.D., Rafic J. Farah, M.D., Seung Tae Lee, M.D., Ph.D., Amynah Pradhan, C.R.N.P., Candis Morrison, Ph.D.,
C.R.N.P., Atekelt Tadese, P.A.-C., Anna Marie Juanitez, R.N., Crystal Lu, Pharm.D., Allison Jacob, M.Sc., Heidi Simmons, Ph.D., Wil-
liam D. Figg, Pharm.D., Seth M. Steinberg, Ph.D., Elaine S. Jaffe, M.D., Mark Roschewski, M.D., Louis M. Staudt, M.D., Ph.D., and
Wyndham H. Wilson, M.D., Ph.D.
The authors’ affiliations are as follows: the Lymphoid Malignancies Branch (C. Melani, R.L., J.D.P., D.W.H., J.S., J.M., Y.Y., W.X.,
A.P., C. Morrison, A.T., A.M.J., M.R., L.M.S., W.H.W.), the Clinical Pharmacology Program (C.J.P., O.A., W.D.F.), the Molecular Imag-
ing Branch (E.M., L.L., E.B.), and the Biostatistics and Data Management Section (S.M.S.), Center for Cancer Research, the Laboratory
of Pathology, Clinical Center (S.P., T.D.-H., S.D.P., E.S.J.), and the Biometric Research Program, Division of Cancer Treatment and
Diagnosis (G.W.), National Cancer Institute, the Division of Pre-Clinical Innovation Chemistry Technologies, National Center for Ad-
vancing Translational Sciences (C.J.T., M.C., F.A.T.), and the Clinical Center Pharmacy Department (C.L.), National Institutes of Health,
Bethesda, and Greenebaum Comprehensive Cancer Center, University of Maryland Medical Center, Baltimore (S.T.L.) — all in Mary-
land; the Division of Hematology and Oncology, University of Virginia, Charlottesville (C.A.P.); Mario Lemieux Center for Blood Can-
cers, University of Pittsburgh School of Medicine, Pittsburgh (R.J.F.); and Adaptive Biotechnologies, Seattle (A.J., H.S.).
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new england

Combination Targeted Therapy in Relapsed Diffuse

n engl j med 390;23 nejm.org June 20, 2024 2143

2144 n engl j med 390;23 nejm.org June 20, 2024

The New England Journal of Medicine

n engl j med 390;23 nejm.org June 20, 2024 2145

A Targeted Survival Pathways B Treatment and Follow-up

Prednisone GR IKZF1 IKZF3

COO (RNA) GCB Unclassified

LymphGen MCD BN2 A53

2146 n engl j med 390;23 nejm.org June 20, 2024

The New England Journal of Medicine

n engl j med 390;23 nejm.org June 20, 2024 2147

Table 1. Characteristics of the Patients at Baseline.*

Dose Levels 1–4, DLBCL, Total

2148 n engl j med 390;23 nejm.org June 20, 2024

The New England Journal of Medicine

Increased Creatinine Level 22

Increased ALT Level 17 22

Figure 2. Adverse Events.

n engl j med 390;23 nejm.org June 20, 2024 2149

Table 2. Response and Survival.

Progression-free Overall Survival

no./total no. (%) % (95% CI)

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B Duration of Response to ViPOR

those with an unclassified DLBCL subtype (3 of 20

fer sensitivity to ViPOR (Fig. 4B). To test this 0 6 12 18 24 30 36 42 48 54

hypothesis, we measured the cytotoxicity of the Months

n engl j med 390;23 nejm.org June 20, 2024 2151

difference in sensitivity of GCB genetic subtypes Discussion

Complete response Partial response Stable disease Progressive disease

Figure 4. Molecular Correlates of ViPOR Response.

2152 n engl j med 390;23 nejm.org June 20, 2024

The New England Journal of Medicine

synergy, we designed a schedule reminiscent of (HGBCL-DH-BCL2), with a higher 2-year progres-

n engl j med 390;23 nejm.org June 20, 2024 2153

2154 n engl j med 390;23 nejm.org June 20, 2024

The New England Journal of Medicine

n engl j med 390;23 nejm.org June 20, 2024 2155

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