CLINICAL NEWS
On Location Lymphoma Biology
R-EPOCH May Be Viable Option for Patients with High-Risk DLBCL
Results from a single-center study show that
the combination of etoposide and standard
R-CHOP chemotherapy (R-EPOCH) leads
to a high overall response rate (ORR) in
patients with high-risk diffuse large B-cell
lymphoma (DLBCL). Researchers also
found that rates of complete response (CR)
were higher among patients who received
dose-adjusted R-EPOCH.
Up to 40 percent of patients with
DLBCL who receive standard R-CHOP will
relapse following treatment, lead author
Vishwanath Sathyanarayanan, MD, from
the University of Texas MD Anderson Cancer Center, explained. Earlier clinical trials
have shown that R-EPOCH (rituximab,
etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin) improves
outcomes in patients with DLBCL, and the
combination is being compared with RCHOP in an ongoing phase III clinical trial.
Dr. Sathyanarayanan and colleagues
conducted a retrospective review of patients
treated with R-EPOCH at MD Anderson
Cancer Center between 2010 and 2014.
Results from this real-world population
were presented at the 2016 ASH Meeting on
Lymphoma Biology.
“This is one of the largest retrospective
studies to assess the response to R-EPOCH
in patients with newly diagnosed DLBCL
with dose-adjusted chemotherapy,” Dr.
Sathyanarayanan told ASH Clinical News.
“R-EPOCH is a highly effective regimen in
patients with high-risk DLBCL, and it may
allow us to reach a higher cure rate than
with R-CHOP alone, though further studies
are needed.”
Researchers analyzed demographic,
prognostic, and treatment variables, compared with clinical response and survival
outcomes in 205 patients (median age =
59 years; range = 22-86 years). Patients
with secondary central nervous system or
double-hit lymphoma were excluded from
this analysis.
Many of the patients were considered
high-risk: 48 percent of patients had an
International Prognostic Index (IPI) score
of 3-5, 30 percent had non-germinal center
subtype (non-GCB), and 75 percent had
Ki-67 expression ≥80 percent.
In contrast with earlier data, survival
was similar regardless of specific risk factors,
which suggests that R-EPOCH may help
negate poor prognosis, according to Dr.
Sathyanarayanan. “In previous studies, the
benefit was mainly evident in the germinal
center sub-type due to suppression of BCL-6
by infusional etoposide,” he said. “We found
GCB and non-GCB subgroups had similar
outcomes.”
This analysis excluded patients with
double-hit lymphomas, but he noted
that the benefits of R-EPOCH are similar
between patients with and without doubleprotein-expression lymphoma.
The authors reported an ORR of 95.5
percent, with 89.6 percent of patients
achieving a CR.
Patients fared significantly better when
R-EPOCH was dose-adjusted based on their
absolute neutrophil count (ANC) nadir (if
the nadir ANC >500/uL, doses of etoposide,
doxorubicin, and cyclophosphamide for the
next cycle are all increased by 20%), with 94
Tazemetostat for Patients with
Pretreated Non-Hodgkin Lymphoma
Preliminary data from an ongoing, global, phase II trial of tazemetostat, a first-in-class EZH2
inhibitor, in patients with relapsed or refractory non-Hodgkin lymphoma (NHL) showed
“encouraging” safety and efficacy, according to lead author Franck Morschhauser, MD,
PhD, who presented the findings at the 2016 ASH Meeting on Lymphoma Biology.
“These patients, especially those with highly refractory disease or multiple relapses, are
in need of new options,” Dr. Morschhauser, from Hôpital Claude Huriez in Lille, France, told
ASH Clinical News. “Preliminary findings suggest that continued tazemetostat treatment has
the potential to translate into tumor regression over a prolonged period of time.”
Dr. Morschhauser said that results from this open-label, two-stage study are consistent
with the earlier phase I study in which researchers observed many patients who had partial
responses moving to complete responses over time.
The ongoing phase II trial is evaluatin g tazemetostat 800 mg taken orally twice daily in
patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) or follicular lymphoma (FL) with mutated or wild-type EZH2. All patients had relapsed/refractory disease
following at least two prior treatment regimens (including at least 1 alkylator and anti-CD20based regimen); DLBCL patients were included if they were considered unable to benefit
from autologous hematopoietic cell transplantation.
The study’s primary endpoint is objective response rate (including complete response
[CR], partial response [PR], and stable disease [SD]) assessed every eight weeks for the first
six months and every 12 weeks thereafter. Secondary endpoints include progression-free
survival, duration of response, and safety/tolerability.
34
ASH Clinical News
percent of dose-adjustTABLE 3. Response and Survival Rates Based
ed patients achieving
on High-Risk Features
a CR compared with
Overall
3-Year Overall
p Value
83 percent of those
Variable
response rate
Survival
(ORR/
whose regimen was not
(ORR), n (%)
(OS; 95% CI)
OS)
adjusted (p value not
International Prognostic Index score
reported).
1
62 (98)
0.98 (0.95-1)
At a median follow
up of 2.8 years, the
2
42 (96)
0.85 (0.75-0.97)
0.4/0.01
median overall survival
3-5
90 (94)
0.8 (0.72-0.89)
(OS) and progressionCell of origin
free survival (PFS) had
Germinal
not yet been reached,
97 (94)
0.87 (0.8-0.94)
center subtype
even among patients
0.7/0.3
Non-germinal
with IPI scores 3-5
59 (97)
0.9 (0.83-0.99)
center subtype
(TABLE 3). Again,
more patients who
Ki67 expression ≥80%
received dose-adjusted
No
43 (98)
0.8 (0.7-0.95)
0.7/0.3
R-EPOCH were alive at
Yes
126 (95)
0.89 (0.84-0.95)
three years, compared
CD 5115 (97)
0.87 (0.81-0.94)
with an unadjusted
0.26/0.73
CD5+
23 (91)
0.87 (0.74-1)
regimen: 92 percent
versus 80 percent (p
CD 3067(91)
0.84 (0.75-0.94)
0.66/0.85
value not reported).
CD 30+
28(97)
0.81 ( 0.67- 0.98 )
The treatment was
MYC+/BCL 210 (100)
1 (1-1)
1.00/0.51
“relatively well tolerMYC-/BCL2+
13
(92.3)
0.85
(0.67-1)
1.0/0.51
ated,” according to the
authors. Forty-seven
Adjusted Dosing
patients (23%) were
No
49 (93)
0.8 (0.69-0.92)
0.03/NA
admitted for neutropeYes
120 (99)
0.92 (0.87-0.98)
nic fever, which, they
noted, is in line with
earlier studies.
REFERENCE
Authors caution that this is a small,
Sathyanarayanan V, Issa AK, Ahmed MA, et al. DA-EPOCH-R for high
retrospective study, noting that data from
risk diffuse large B-cell lymphoma (DLBCL): The University of Texas MD
the randomized, phase III trial of R-CHOP
Anderson Experience. Abstract #88556. Presented at the 2016 ASH
Meeting on Lymphoma Biology, June 20, 2016; Colorado Springs, CO.
versus R-EPOCH expected later this year
will help shed more light on their findings.
Dr. Morschhauser presented interim results for 47 patients who had evaluable efficacy data
available by the cut-off date. Patients were stratified into five cohorts based on tumor subtype:
• EZH2-mutated DLBCL with germinal center B-cell (GCB) subtype (n=5): 1 PR and 2 SD
• DLBCL with GCB subtype and wild-type EZH2 (n=19): 2 CR, 1 PR, and 6 SD
• DLBCL with non-GCB subtype (n=20): 2 CR, 4 PR, and 5 SD
• FL with EZH2 mutations (n=3): 3 PR
The fifth cohort included patients with FL with wild-type EZH2, but assessment data were not
available at the cut-off date and were not included in this analysis.
At the cut-off date, the four patients who achieved a CR and the majority of patients who
achieved a PR or SD as a best response were still on tazemetostat treatment.
“Consistent with the phase I experience, the frequency of grade ≥3 treatment-emergent
adverse events (TEAEs) is low at 16 percent,” the authors reported. The most common
TEAEs (≥5%) were nausea, asthenia, thrombocytopenia, neutropenia, and fatigue; seven
of these AEs were grade 3 or higher. Safety is “critically important as we consider treating
patients over an extended period of time,” Dr. Morschhauser said. “In addition, we have
seen a strong correlation between tazemetostat treatment and clinical benefits in patients,
even in those who have been heavily pre-treated.”
“Patients continue to be followed for clinical outcomes in light of observations from
phase I that the onset of clinical response may occur over as many as 10 months and continue to improve for patients who remain on treatment,” the authors concluded. ●
REFERENCE
Morschhauser F, Salles G, McKay, P et al. Initial report from a phase 2 multi-center study of tazemetostat (EPZ-6438), an inhibitor of enhancer of Zeste-Homolog 2 (EZH2), in patients with relapsed or refractory B-cell non-Hodgkin lymphoma (NHL). Abstract #88525. Presented at the 2016 ASH Meeting on Lymphoma
Biology, June 20, 2016; Colorado Springs, CO.
August 2016